Cellular immunity with interferon gamma production could have a role in protection from hepatitis C virus (HCV). Interleukin (IL)-12 is a key cytokine in promoting such anti-viral T helper 1 (Th1) responses. We hypothesized that a genetic background able to promote cellular responses may be associated with apparent protection from infection and have investigated the distribution of the functional 1188A/C polymorphism of IL-12B in HCV exposed but uninfected cases. The frequency of the high IL-12-producing C allele was determined by restriction enzyme genotyping in 76 exposed–uninfected individuals and 105 healthy controls. Overall, the C allele was found in 27·6% of exposed–uninfected cases compared with 16·7% of healthy controls [χ2 = 6·3, P = 0·02, odds ratio (OR) = 1·9, 95% confidence interval (CI) = 1·1–3·2]. CC genotype was found in 10·5% of exposed–uninfected cases compared with 0·9% controls (χ2 = 9·3, P = 0·01, OR = 12, 95% CI = 1·5–100). Individuals at high risk of HCV infection yet who remain uninfected may be resistant in some way to infection. In our cohort of exposed–uninfected cases a genetic background of enhanced IL-12 production was associated with apparent resistance to HCV infection. This lends support to a central role for cellular immune responses in protecting from infection.