Adherence to the Mediterranean diet (MedDiet) has long been associated with several health benefits, including a reduced risk of heart disease, diabetes, and obesity. The MedDiet is characterized by a high consumption of foods such as fruits, vegetables, whole grains, fish, and olive oil, along with a moderate intake of red meat and red wine with meals. Some studies report significant differences between men and women in susceptibility to obesity, with women at a higher prevalence of obesity than men. One unexplored aspect, however, concerns the sex difference in MedDiet adherence, which could be influenced by various factors, such as health perceptions, food preferences, and cultural influences. The aim of this study is to assess the effectiveness and impact of MedDiet adherence in men and women, with a focus on its influence on health and well-being, as well as its ability to promote sex equity in healthcare outcomes. Moreover, we aim to measure the overall health improvements in men and women participating in a MedDiet program, including changes in body composition and overall quality of life. This study highlights that the MedDiet is associated with more significant body weight loss in women, although their increase in MedDiet adherence was lower than in men. Trial registration: NCT01890070. Registered 24 June 2013.