In healthy subjects, previous studies have demonstrated a great interindividual variability in the ability for tumor necrosis factor-α (TNF-α) production. The gene for TNF-α is closely linked to and located in the major histocompatibility complex (MHC) and it has been suggested that these interindividual differences may be HLA related. Since TNF-α is likely to be an important mediator in renal allograft rejection, we investigated the role of HLA antigens on TNF-α production rates by peripheral blood mononuclear cells (PBMC) from renal transplant recipients during stable graft function. HLA-DR2-positive recipients showed significantly lower spontaneous TNF-α production than DR2-negative patients (p < 0.001). Upon stimulation with OKT3, HLA-DR2-positive patients also showed significantly lower TNF-α production than DR2-negative subjects (p < 0.001). HLA-DR3-positive recipients, however, showed significantly higher spontaneous TNF-α production than DR3-negative individuals (p < 0.05). These results suggest that differences in TNF-α production, both spontaneous and induced, may be due to the expression of certain DR allotypes.