<b><i>Background/Aims:</i></b> The aim of our study was to evaluate the influence of lifestyle factors and molecular biomarkers on the maintenance of the weight lost after a hypocaloric Mediterranean diet. <b><i>Design:</i></b> After 3 months on a diet, patients (<i>n</i> = 335) remained with no controlled diet during 3 years and they were revaluated. <b><i>Results:</i></b> Using linear regression, in the group of responders, we detected that a positive weight loss at 3 months, serum levels of leptin at 3 months, and each 30 min per week of physical activity were associated with weight loss maintenance. In the model with reduced weight (RW) as dependent variable, a positive weight loss at 3 months was associated with 2.4% RW (95% CI 1.31–8.11; <i>p</i> = 0.015), each unit of serum leptin levels at 3 months with –0.44% RW (95% CI –0.59 to –0.020; <i>p</i> = 0.007), each basal unit homeostasis model assessment for insulin resistance (HOMA-IR) level with –2.32% (95% CI –13.01 to –0.17; <i>p</i> = 0.040), and each 30 min per week of physical activity with 1.58% RW (95% CI 1.08–2.94; <i>p</i> = 0.020). <b><i>Conclusion:</i></b> Obese subjects who are on maintenance weight loss after a dietary intervention appear to have a better initial response during the 3 months intervention, more physical activity at 3 years, and lower basal HOMA-IR and leptin after weight loss than those who regain weight.