The Portrait of Pope Leo X with two Cardinals is a painting by the Italian High Renaissance master Raphael, c. 1517. It is housed in the Uffizi Gallery of Florence.

In contrast to works depicting classical, idealised Madonnas and figures from antiquity, this portrait shows the sitter in a realistic manner. The Pope is depicted with the weight of late middle age, while his sight appears to be strained. The painting sets up a series of visual contradictions between appearance and reality, intended by Raphael to reflect the unrest of a period of turmoil for the papacy. Martin Luther had recently challenged papal authority, listing among other grievances, Leo X's method of selling indulgences to fund work on St Peter's.

The pommel on top of the Pope's chair evokes the symbolic abacus balls of the Medici family, while the illuminated Bible open on the table has been identified as the Hamilton Bible.

The cardinals are usually identified as Giulio di Giuliano de' Medici and Luigi de' Rossi.

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