Hepatitis C (HCV) recurrence after liver transplantation is universal although severity varies. We explored whether certain donor cytokine gene polymorphisms may be useful markers of susceptibility to severe recurrence. Allograft tumor necrosis factor (TNF)  and interleukin (IL) 16 gene polymorphisms were correlated with l-yr clinical outcome among HCVϩ recipients. Recipients of donor TNF 2,2 (n ϭ 8) experienced less recurrence (50% vs. 71%, P Ͻ 0.05), less fibrosis (25% vs. 76%, P Ͻ 0.01), and less rejection (25% vs. 71%, P Ͻ 0.01) than donor TNF 1,1 (n ϭ 19). Recipients of donor TNF 1,2 (n ϭ 27) demonstrated an intermediate picture with less fibrosis (56%, P Ͻ 0.01) and less rejection (37%, P Ͻ 0.01) than TNF 1,1 . Recipients with donor IL16 TC (n ϭ 22) showed less recurrence (65% vs. 78%, P ϭ 0.05), less fibrosis (53% vs. 67%, P ϭ 0.06), and less rejection (41% vs. 55%, P ϭ 0.06) than IL16 TT (n ϭ 32) genotype. Recipients of the combination TNF 2,2 /IL16 TC donor genotype had the most benign clinical outcome with less recurrence (33% vs. 75%, P Ͻ 0.01), no fibrosis (0% vs. 50%, P Ͻ 0.001), and fewer rejections (33% vs. 75%, P Ͻ 0.01) than donor TNF 1,1 /IL16 TT genotype. In vitro production of cytokines correlated with genotype. Release of soluble TNF for TNF 1,1 vs. TNF 1,2 and TNF 2,2 was 4803 Ϯ 2142 pg/mL vs. 5629 Ϯ 3106 (P ϭ not significant [ns]) and 7180 Ϯ 3005 (P ϭ ns). Release of soluble IL16 for IL16 TT vs. IL16 TC was 437 Ϯ 86 pg/mL vs. 554 Ϯ 39 (P ϭ 0.06). In conclusion, allograft TNF and IL16 gene polymorphisms may be useful markers to predict the severity of disease recurrence among HCVϩ patients after liver transplantation.