Purpose: Adiponectin gene variations have been associated with obesity. There are few interventional studies analyzing this association. The aim of this study was to analyze the effects of a nutritional intervention with Mediterranean-style diet and three (-4034A/C, +45T/G, and +276 G/T) adiponectin gene variants on 3-year body weight changes in high cardiovascular risk patients. Subjects and methods: A total of 737 participants, aged 55-80 at high cardiovascular risk were assigned to a low-fat diet or to a Mediterranean-style diet (MD) groups, one with high intake of virgin olive oil (VOO) and the other with high intake of nuts. Anthropometric parameters were taken at baseline and after 3-year follow-up, and the genotyping of the -4034A/C, +45T/G, and +276 G/T polymorphisms was done. Results: GG genotype of the +45T/G polymorphism was associated with 3-year higher body weight gain (B = 1.399; B = 0.043). TT genotype of the +276G/T polymorphism was linked to the highest 3-year body weight gain in men. Both Mediterranean diets appeared to reverse this effect (p for interaction = 0.053). Conclusion: Adiponectin gene variation appeared to be associated with 3-year body weight changes in a high cardiovascular risk population. This association may be modulated by a nutritional intervention with a Mediterranean-style diet.