Genomic DNA was obtained from peripheral blood samples of patients JB and DS each of whom received a kidney transplant at 16 years of age from a serologically HLA-DR matched and HLA-class I -mismatched donor. Both patients discontinued immunosuppression after 1-2 years and retained good renal function for an additional 5 years or more. DNA was analyzed for genetic polymorphisms in the tumor necrosis factor-α (TNFα) and tumor growth factor-β1 (TGFβ1) loci. Biopsy samples obtained during stable function (DS, JB) and during rejection (JB) were analyzed by RT/PCR for cytokine gene expression. Both patients had a high responder genotype for TGFβ1. DS had a low responder TNFα genotype, while JB and his donor were both genotypically TNFα intermediate responders. DS had a high TGFβ1: TNFα mRNA ratio in two biopsies obtained during tolerance, while JB, who eventually lost his graft, had more TNFα than TGFβ1 mRNA. The results suggest a possible role for cytokine immunogenetics in the stability of peripheral tolerance.