[citation needed] Comastri served as vice-rector of the minor seminary of Pitigliano and, at the same time, did pastoral work in the parish of San Quirico'.

He was also a member of the diocesan college of consultors, and served as episcopal delegate for the seminarians residing outside of the diocese and professor of religion at the Professional Institute for Maritime Activities in Porto Santo Stefano.

[2] He received his episcopal consecration on 12 September from Cardinal Bernardin Gantin, with Archbishop Gaetano Bonicelli and Bishop Eugenio Binini serving as co-consecrators, in the parish church San Stefano Protomartire.

[5] He preached the Lenten spiritual exercises for Pope John Paul II and the Roman Curia in 2003 and the meditations for the Stations of the Cross in the Colosseum on Good Friday 2006.

[7] Pope Benedict XVI created him a cardinal in the consistory of 24 November 2007,[8] assigning him the titular church of San Salvatore in Lauro with the rank of cardinal-deacon.

[12] In a 2020 television interview, Comastri objected to Turkey's decision to turn Hagia Sophia, once a church and long a museum, into a mosque.