Clostridium piliforme induces enterohepatic disease in many domestic and laboratory animal species. Susceptibility to infection is known to vary with the immune status and strain of the host, but little is known about specific immune mechanisms that regulate this disease. To evaluate host control of C. piliforme infection, we examined the role of interleukin-12 (IL-12) both in the control of and in the response to murine C. piliforme infection. For this study, 3-week-old C. piliforme-resistant C57BL/6 or -susceptible DBA/2 mice were infected intravenously with either the toxic H1 or the nontoxic M1 C. piliforme isolate. Serum and liver samples were collected prior to C. piliforme inoculation (day 0) and at days 1, 3, 7, 14, and 28 postinoculation. Evaluation of hepatic IL-12 p40 mRNA expression by reverse transcription-PCR and of total-IL-12 protein levels in serum by enzyme-linked immunosorbent assay revealed that C. piliforme induced elevations in both hepatic p40 mRNA and serum total-IL-12 levels at all times postinoculation. Elevations were similar with both toxic and nontoxic C. piliforme isolates. Levels of total IL-12 in serum were significantly (P < 0.05) higher in C57BL/6 mice than in DBA/2 mice. Additional experiments were performed in which polyclonal antibody treatment was used to neutralize IL-12 in mice of both strains prior to intravenous inoculation with toxic C. piliforme H1. IL-12 neutralization increased the severity of Tyzzer's disease at day 3 postinoculation in both mouse strains, but the degree of increase was greater in C57BL/6 mice than in DBA/2 mice.