Cardiovascular disease (CVD) represents the main cause of morbidity and mortality after renal transplantation. In view of the modern paradigm of atherosclerosis as an inflammatory disease, this study investigated the impact of inflammatory cytokine polymorphisms on posttransplant CVD. The association between cytokine polymorphisms and CVD was assessed in a case-control study to identify the differences in genotype distributions between kidney allografts with or without posttransplant CVD. To validate our results in two independent groups, we divided a cohort of 798 renal transplant recipients according to geographic area: an evaluation cohort of 478 patients from Emilia-Romagna and a validation cohort of 320 patients from the rest of Italy. Tumor necrosis factor (TNF)-alpha, transforming growth factor-beta1, interleukin (IL)-10, IL-6, interferon-gamma, and IL-8 polymorphisms were analyzed, and thereafter, the cytokine production genotype was assigned. In the evaluation cohort, the patients in the CVD and no-CVD groups differed significantly in TNF-alpha and IL-10 genotype frequencies. Using multivariate analyses to test the association with CVD, the TNF-alpha high-producer genotype was associated with a significantly increased cardiovascular risk (odds ratio OR=4.41, 95% confidence interval (CI)=2.53-7.67). Conversely, the IL-10 high-producer genotype resulted protective against CVD (OR=0.07, 95% CI=0.02-0.29). These findings were confirmed in the validation cohort where the carriers of the TNF-alpha high-producer genotype proved to be at 2.45-fold increased cardiovascular risk (OR=2.45, 95% CI=1.29-4.63), whereas the IL-10 high-producer genotype was associated with a 0.08-fold reduced risk (OR=0.08, 95% CI=0.02-0.36). This work suggests a prognostic value of TNF-alpha and IL-10 genotypes, which might represent cardiovascular risk markers in renal transplant.