James was the 3rd son of Infante Pedro, Duke of Coimbra, and Isabella of Urgell; among other kinships he was the great-grandson of the English prince John of Gaunt.

On his aunt’s advice, he traveled to Rome, where Pope Nicholas V, hearing of the disgraces inflicted upon his family after Alfarrobeira, resolved to appoint the young James as the new Archbishop of Lisbon, which had been recently vacated by the death of D. Luís Coutinho.

Given the political situation in Portugal, James was unable to return to Lisbon to take possession of it, and so remained in Italy and governed his archdiocese from afar, via the vicar-general Luís Anes.

While travelling from Rome to Austria to rally support for a new crusade, James of Portugal fell ill and died in Florence on 27 August 1459, at the age of twenty-six.

[6] Some of the best artists in Renaissance Florence were commissioned to design and decorate the chapel of the "Cardinale del Portogallo" in San Miniato, including the Cardinal of Portugal's altarpiece by the Pollaiuolo brothers.