In March 1923 Luzio was sent to Ireland by Pope Pius XI in order to investigate and report on the situation there; this mission was at least partly due to a visit to Rome in December 1922 to January 1923 of two republican delegates, Arthur Clery (qv) and Conn Murphy, who presented a formal complaint alleging that the Irish bishops had exceeded their authority in excommunicating opponents of the treaty. Neither the government of William Cosgrave (qv) nor the Irish hierarchy received the news of Luzio's embassy with enthusiasm. The government feared that it would be perceived as signalling Vatican dissatisfaction with the Irish bishops’ support for the treaty and thereby encourage the republicans. These misgivings were reinforced when the republicans claimed that the pope had sent Luzio as a mediator and thus regarded both sides in the civil war as possessing equal legitimacy: by contrast the Cosgrave administration held that it was a lawfully elected government suppressing a minority rebellion, and was morally entitled to take draconian security measures in defence of its authority. The bishops suspected that the visit heralded the appointment of a permanent nuncio, whose primary concern would be not with Irish affairs but with the use of Ireland as a base to strengthen Vatican diplomatic relations with the British empire. Such a nuncio, the bishops believed, might pre-empt Irish episcopal decisions in a manner owing less to Irish conditions than to Roman preoccupations; further, he might come under the influence of powerful English catholics, seek to secure the appointment of pro-British bishops in Ireland, and thereby undermine popular support for the Irish church. (These fears were coloured by memories of the visit of Archbishop Ignatius Persico to Ireland in 1887 and the subsequent papal condemnation of the Plan of Campaign.)
Luzio arrived at Dublin on 19 March 1923 and on the 21st presented his credentials to Cardinal Michael Logue (qv) at Armagh; these entrusted him with the task of consulting the Irish bishops and obtaining fuller information on the situation than could be secured by letter. On 6 April he had a clandestine meeting with de Valera, arranged by Arthur Clery and the Holy Ghost Fathers of Blackrock College; Luzio subsequently corresponded with de Valera through the Holy Ghost provincial, Father Byrne. De Valera assured Luzio of his loyalty to the church and complained of the denial of the sacraments to republicans (this last discipline was subsequently relaxed, possibly through Luzio's influence). Luzio unsuccessfully attempted to persuade de Valera to order a ceasefire, to accept the result of an election or referendum on the treaty, and to enter the dáil, taking the oath in the same manner that republican deputies in Italy took a parliamentary oath of allegiance. De Valera complained that Luzio did not recognise the extent to which these were matters of principle; in general, however, republicans who met Luzio considered him open to their views.
Luzio's involvement annoyed the government, which claimed that it had to go to considerable trouble in its periodic arrests of republican suspects to avoid the political embarrassment of detaining Luzio. It resented the fact that he had met de Valera before approaching government representatives – Luzio paid a courtesy call to Cosgrave on 11 April. The government was further annoyed when numerous local bodies passed republican-inspired motions calling on Luzio to negotiate a peace settlement, a move that was indiscreetly encouraged by Luzio's secretary, Canon Conry. Kevin O'Shiel (qv) advised the government that the Ulster unionists were presenting Luzio's activities as proving their contention that the Irish Free State was tantamount to ‘Rome rule’. The Freeman's Journal published an article (generally believed to have been inspired if not written by the minister for home affairs, Kevin O'Higgins (qv)) questioning the extent of Luzio's authority, which led an offended Logue to publish the letter sent with Luzio by the papal secretary of state. (The Freeman subsequently published another thinly veiled attack on Luzio, implying that he had shown discourtesy to the government.) Desmond Fitzgerald (qv), minister for external affairs, sent a representative to the pope to demand Luzio's recall, and visited the Vatican himself from 30 April to 4 May. Luzio left Ireland on 6 May 1923; in a farewell message he expressed good wishes for Ireland, describing it as his ‘second fatherland’.
The pro-republican Catholic Bulletin, which regularly portrayed the Cosgrave government as pseudo-catholic stooges of freemasonry, claimed that the pope had sent Luzio to bring peace through mediation, but that this noble intention had been frustrated by British unwillingness to consent to the modification of the treaty; it complained that the government had shown unbecoming indifference towards the papal representative, and that ‘a section’ of its supporters had treated Luzio as if he had been a delegate from ‘the Imperial Wizard of the Ku Klux Klan’. This bitterness at his treatment by the government was shared by Luzio, who complained to clerical friends in Rome that he felt lucky to have escaped with a whole skin and that he regarded Kevin O'Higgins as ‘the incarnation of evil’ (Murray, 184). He is also alleged to have complained that the Irish bishops regarded themselves as ‘twenty-six popes’ (Keogh, 28).
Luzio's later life is obscure, but he was still alive in 1934, when he met Frank Aiken (qv) and his wife on their honeymoon in Rome.