Immune response regulation by cytokines is a key to understanding AGR. The influence of the functional polymorphisms in genes coding for TNF-alpha (-308G > A), IL-10 (-819C > T, and -1082A > G), IFN-gamma [(CA)n], TGF-beta1 (+869T > C), and iCAM-1 (R241G and E469K), in addition to HLA and gender matching on the presentation of AGR in 51 pediatric renal recipients during a 36-month post-transplantation follow-up were analyzed. Also, donors and a control group were genotyped. All groups were within Hardy-Weinberg equilibrium for all polymorphisms except IL-10-819C > T and TNF-alpha (p < 0.005 and p < 0.01, respectively) in recipients. Transplants with gender mismatch showed a higher risk for AGR than those between individuals with gender match (OR, 4.227; p = 0.010). Recipients with a high-production compared with low-production TNF-alpha allele experienced earlier AGR (p = 0.030), and those with high-production alleles of both TNF-alpha and IFN-gamma showed a further increased risk (OR = 11.129, p = 0.024). These findings support the notion that a single genotype cannot by itself explain an event as complex as AGR. The sum or combination of different specific alleles of these genes could better account for the immune response to an allograft.