Marguerite Louise d'Orléans, a granddaughter of Henry IV of France, was married to Cosimo by proxy on 17 April 1661 at the Palais du Louvre. She arrived in Tuscany on 12 June, disembarking at Livorno, and made her formal entry to Florence on 20 June to much pageantry. As a wedding gift, Grand Duke Ferdinando presented her with a pearl the "size of a small pigeon's egg."
The marriage was unhappy from the start. A few nights following the formal entry, Marguerite Louise demanded the Tuscan crown jewels for her own personal use; Cosimo refused. The jewels that she did manage to extract from Cosimo were almost smuggled out of Tuscany by her attendants but for the efforts of Ferdinando's agents. Marguerite Louise's extravagances perturbed Ferdinando because the Tuscan exchequer was nearly bankrupt; it was so empty that when the Wars of Castro mercenaries were paid for, the state could no longer afford to pay interest on government bonds. Accordingly, the interest rate was lowered by 0.75%. The economy, too, was so decrepit that barter trade became prevalent in rural market places. In August 1663 Marguerite Louise delivered a boy: Ferdinando. Two more children followed: Anna Maria Luisa in 1667 and Gian Gastone in 1671.
Ferdinando beseeched Louis XIV to do something about his daughter-in-law's behaviour; he sent the Comte de Saint Mêmê. Marguerite Louise wanted to return to France, and Mêmê sympathised with this, as did much of the French court, so he left without finding a solution to the heir's domestic disharmony, incensing both Ferdinando and Louis XIV. She humiliated Cosimo at every chance she got: she insisted on employing French cooks, as she feared the Medici would poison her. In September 1664 Marguerite Louise abandoned her apartments in the Pitti, the grand ducal palace. Cosimo moved her into Villa Lapeggi. Here, she was watched by forty soldiers, and six courtiers, appointed by Cosimo, had to follow her everywhere. The next year she reconciled with the grand ducal family, and gave birth to Anna Maria Luisa, future Electress Palatine, in August 1667. The delicate rapprochement that existed between Marguerite Louise and the rest of the family collapsed after Anna Maria Luisa's birth, when Marguerite Louise caught smallpox and decided to blame Cosimo for all her problems.