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With her birth her father saw her as an opportunity to renew an alliance with France (Louis XII was his former brother-in-law), therefore in 1523 it was decided that she would marry the heir to the throne, Prince Francis of France. She was raised in France and was married to Francis in 1534, soon they had their first son who became Louis XIII. Not long after the family happiness was crushed as tuberculosis killed the king, their brother-in-law and his wife. They adopted their niece Margaret and she was raised as Louis's sister.
Mary was a good queen to the French and Francis II was liked as a good king. In 1543 she went to England as a visitor to her brother's coronation. She didn't live to become the Queen Mother to Louis as she died of an illness in 1561 but she was buried with honors in the Basilica of St Denis in Paris. In 1573 her husband asked to be buried next to her and to add a carving on the tomb saying: C'est là que réside la plus grande reine France ait jamais eu (Here lies the Greatest Queen France ever had).