Insulin resistance is closely associated with numerous metabolic disorders. Although studies have supported the importance of insulin resistance in carcinogenesis, the existing data have not established its relevance in the context of lung cancer. The aim of the present case-control study was to evaluate the association between insulin resistance and lung cancer after adjusting for possible confounders. Homeostasis model assessment of insulin resistance (HOMA-IR) and serum leptin and adiponectin levels were determined in 81 lung cancer cases and 162 age- and sex-matched controls; anthropometric and lifestyle variables were recorded. Mean HOMA-IR in the cases was more than 2-fold higher compared with the mean value of controls (P < .001). Among controls, HOMA-IR correlated positively with serum leptin (r = 0.16; P = .04), body mass index (r = 0.43; P = .0001), and waist-to-hip ratio (r = 0.21; P = .01) but negatively with serum adiponectin (r = −0.29; P = .0002). As expected, smoking was associated with an approximately 10-fold increase in lung cancer risk in multiple logistic regression models. A positive association between HOMA-IR, treated as continuous variable, and lung cancer (odds ratio [OR] = 1.52, 95% confidence interval [CI]: 1.16-1.99, P = .002, model 1) was demonstrated, which persisted after adjustment for somatometric and lifestyle variables (OR = 2.36, 95% CI: 1.00-5.55, P = .05, model 2). When serum adiponectin was also taken into account, the association seemed fairly robust (OR = 2.58, 95% CI: 1.11-6.01, P = .03, model 3); on the contrary, when serum leptin was added, the association remained positive, but lost its statistical significance (OR = 1.76, 95% CI: 0.78-3.98, P = .17, model 4). In the fully adjusted model, HOMA-IR was still positively, but only marginally, associated with lung cancer risk (OR = 2.02, 95% CI: 0.88-4.65, P = .10, model 5). Insulin resistance may represent a meaningful risk factor for lung cancer.