To ascertain whether single nucleotide polymorphisms (SNPs) regulating the expression of interferon-gamma (IFN-gamma), IFN-gamma receptor-1 (IFNGR-1), interleukin-6 (IL-6), IL-10, IL-18, and tumor necrosis factor-alpha (TNF-alpha) may be associated with early fibrosis progression of recurrent hepatitis C, 50 liver transplantation recipients (32 men, 18 women, median age 56 years) with a median histologic follow-up time of 54 months were studied; 98 healthy blood donors served as controls. Cytokine SNPs were determined by means of previously described PCR-based methods. On the basis of the SNP studies, a low, intermediate, or high producer cytokine phenotype was attributed to each patient. Only 1 of the 17 low IL-10 producers reached an Ishak staging score > 2, in contrast to 20 of the 33 patients who were intermediate or high IL-10 producers (Mantel-Cox, p < 0.005). Recipients who were low IL-10 producers and high IFN-gamma producers had significantly slower fibrosis progression in comparison to intermediate/high IL-10 producers and low IFN-gamma producers (p < 0.005). In conclusion, cytokine SNPs resulting in high and low producer phenotypes of both Th1 and Th2 cytokines appear to modulate the course of recurrent hepatitis C. Low IL-10 producers are those with the slowest histologic fibrosis progression.