African-American race is associated with an increased risk of allograft loss, suggesting that African-American patients may form an immunologically higher risk group. Previously, we demonstrated that immune cell costimulatory molecule expression is significantly higher in African-Americans than in Caucasians. Polymorphic variations in the genes for cytokines have been associated with a number of immunological conditions, and with transplant rejection. This study was performed to determine the distribution, in African-American and Caucasian renal transplant recipients, of single nucleotide polymorphisms (SNPs) in the following cytokine genes: tumor necrosis factor-α(TNF-α), interferon-γ (IFN-γ) interleukin (IL)-6, IL-10, and transforming growth factor-β (TGF-β). Cytokine production from blood cells was determined, and cell-surface B7 (CD80, CD86) expression was measured. There was a significant link between IL-10 genotype and acute rejection episodes, but only in African-American patients (p <0.01). Also, African-American patients had a significantly higher probability of having the IL-6 G-allele (p <0.0001), which is associated with a high production of IL-6 protein. Incubation of blood cells with IL-6 resulted in increased expression of surface CD80 and CD86, while IL- 10 decreased CD80 expression. This study demonstrated a clear correlation of the IL-6 G-allele with increased cellular CD80 expression and the IL-10 G-allele with decreased CD80 expression. These data raise the possibility that specific genotypes are associated with local cytokine regulation of cell-surface costimulatory molecule expression. African-American patients may have a genetically determined, quantitatively different immune response than Caucasian patients, contributing to adverse transplant outcomes. © 2002 Blackwell Munksgaard.