Obesity, deregulation of adipocytokines, and insulin resistance are interrelated and have been implicated in carcinogenesis. In search of novel risk factors for melanoma, we explored the association of this disease with insulin resistance in a small size, case-control study. Homeostasis Model Assessment for Insulin Resistance (HOMA-IR), serum leptin, and adiponectin levels were determined in 55 patients with incident melanoma and 165 age-matched and sex-matched controls. Odds ratios were derived after adjusting for skin type, medical history, sociodemographic, lifestyle, and anthropometric parameters. Among the controls, HOMA-IR correlated positively with BMI (r=0.34; P=0.0001), waist-to-hip ratio (r=0.20; P=0.01) and negatively with serum adiponectin (r=-0.21; P=0.006), whereas the correlation with leptin was essentially null (r=0.09; P=0.27). The mean HOMA-IR was approximately 1.5 times higher in cases than in controls (P=0.05). The established positive association of melanoma with skin type was evident in multiple logistic regression models and so was the association with increasing HOMA-IR quintile (odds ratio for the fifth quintile=3.68; 95% confidence intervals 1.15-11.79, P=0.02). The latter persisted after adjustment for anthropometric variables and adiponectin but was attenuated when leptin was introduced in the model. These findings point to insulin resistance as a potentially independent risk factor for melanoma and need to be confirmed by future larger studies, ideally allowing the control of the directionality of the association.