His Holiness, the Pope is the Bishop of Rome, head of the Roman Catholic Church, and ruler of the vanished Papal States. Sherlock Holmes has had interactions with this illustrious figure on two occasions: once, in 1892, when he was involved in the affair of the Vatican cameos, and again in 1895, when the Pontiff personally hired him to solve the case of the sudden death of Cardinal Tosca.
Holmes thanks Dr James Mortimer for bringing the case of Sir Charles Baskerville's death to his attention, saying that he lost touch with his English cases in his "anxiety to oblige the Pope" regarding the affair of the Vatican cameos.
John Watson notes that 1895 was a year of exceptionally curious cases, including Holmes "famous investigation of the sudden death of Cardinal Tosca - an inquiry which was carried out by him at the express desire of His Holiness the Pope".
Pope Leo XIII is a central figure in this book, which contains three stories: "The Case of Cardinal Tosca", when Leo engages Holmes to solves the murder of a member of his Curia; "The Vatican Cameos", which involves the theft of a collection of Roman cameos and is told partially from Leo's perspective; and "The Second Coptic Patriarch", where G. K. Chesterton's Father Brown is wrongly imprisoned for the murder of a Coptic cleric.
- According to the dates of the stories he is mentioned in (1889 and 1895), the Pope Holmes interacted with would have been Leo XIII. Leo was well known for his erudite and intellectual nature, as well as for being both the oldest and the longest-serving pope in history.