<b><i>Background/Aims:</i></b> Single nucleotide polymorphisms (SNPs) in the <i>ADIPOQ</i> gene could explain the adiponectin level. However, the knowledge about the influence of genetic and lifestyle factors is not sufficient. The aim was to analyze whether the effect of the -11391G/A SNP in the <i>ADIPOQ</i> gene is modulated by lifestyle factors in Mexican subjects. <b><i>Methods:</i></b> A cross-sectional study was performed in which 394<b> </b>participants were analyzed. Genetic, anthropometric, biochemical, dietary, clinical and physical activity parameters were measured. Statistical analysis was performed with SPSSv19 software. <b><i>Results:</i></b> The distribution of the -11391G/A SNP genotypes was 55.6 and 44.4% for GG and AG, respectively. The adiponectin level was modulated by the -11391G/A SNP in response to the body mass index (BMI); A allele carriers showed a higher adiponectin level compared to G homozygous carriers but only in the minor BMI tertile group (p = 0.032). Adiponectin level variability was explained by gender [(<i>r</i>) = 1.5, 95% CI 1.1-1.9, p = 0.000], insulin resistance [(<i>r</i>)<i> = </i>-1.2, 95% CI -0.8 to -1.6, p = 0.000], physical activity [(<i>r</i>) = 0.6, 95% CI 0.2-0.9, p = 0.002] and monounsaturated fat intake [(<i>r</i>) = 0.5, 95% CI 0.38-1.0, p = 0.047]. <b><i>Conclusions:</i></b> The adiponectin level was modulated by the interaction between BMI and -11391G/A SNP; this suggests that the lifestyle rather than genetic factors modulates serum adiponectin.