Background. Polymorphisms in the regulatory regions of cytokine genes affect protein production and are associated with allograft outcome. Ethnic origin has been identified as a significant prognostic factor for several immune-mediated diseases and for outcomeq after allotransplantation. A clear relationship between cytokine polymorphisms and ethnicity has not been shown. Methods. One hundred sixty subjects including 102 whites and 43 African-Americans were studied. Using polymerase chain reaction-based assays and, in some cases, restriction enzyme digestion, we determined genetic polymorphisms for the cytokines interleukin (IL) -2, IL-6, IL-10, tumor necrosis factor-α, transforming growth factor-β, and interferon-γ (IFN-γ). Genetic polymorphism frequencies were then compared to ethnicity using chi-square analysis and Fisher's exact two-tailed tests. Results. For both the IL-2 and IL-6 genes, we found that whites and African-Americans differed significantly (P<0.05) in their allelic distribution and genotype frequency. A trend toward ethnic distribution was noted among the alleles and genotypes for the IL-10 and IFN-γ genes. We found no correlation between ethnicity and either allelic distribution or genotype frequency for the tumor necrosis factor-α or transforming growth factor-β genes. When comparisons were made between patients with or without a history of kidney failure, the allelic or genotypic distributions for the IL-6 and IFN-≥ genes were found to significantly differ. Conclusions. Our work demonstrates a correlation between ethnicity and polymorphisms in several cytokine genes. In addition, we found that patients requiring renal transplantation differ from the general population with regard to certain cytokine gene polymorphisms. These findings may have relevance in making prognostic determinations or tailoring immunomodulatory regimens after renal transplantation.