Despite the controversy about her illegitimate birth and ambiguous position in the Grand Ducal house, Virginia's older brothers began negotiations with the House of Sforza of a marriage between her and one of his members. In 1581 she was betrothed to Francesco Sforza, Count of Santa Fiora, but the wedding didn't take place because the groom chose the ecclesiastical career and became a Cardinal. After this, it was decided to arrange her marriage with a member of the House of Este with the purpose to improve the relations between both families and break the isolation of the Grand Duchy of Tuscany from the other Italian states. Virginia's half-brother Cardinal Ferdinando has agreed with Cardinal Luigi d'Este for the marriage of his nephew and Virginia. In addition, the second wife of Grand Duke Francesco I, Bianca Cappello, also played a big role in the conclusion of this alliance.