We have previously shown that C3H/HeJ male mice are approximately 20-fold more susceptible to the induction of liver tumors by N-ethyl-N-nitrosourea (ENU) than are C57BL/6J male mice and that this difference in sensitivity is largely determined by a single genetic locus (Hcs, hepatocarcinogen sensitivity). In order to determine whether the Hcs locus affects initiation or promotion of hepatocarcinogenesis, we studied the development of putatively preneoplastic hepatic lesions that are deficient in glucose-6-phosphatase (G6Pase) in mice treated at 12 days of age with ENU. In ENU-treated male mice of both strains, the number and size of G6Pase-deficient hepatic foci increased over time between 12 and 24 weeks of age. However, the rate of growth of the lesions was 1.7 times faster for C3H/HeJ male mice (volume doubling time 2.0 +/- 0.7 weeks) than for C57BL/6J mice (3.4 +/- 0.4 weeks). Although the number and size of G6Pase-deficient foci induced by ENU treatment of female C3H/HeJ and C57BL/6J mice were smaller than for foci in similarly treated male mice, there was no significant difference between the growth rates of the foci in female C3H/HeJ and C57BL/6J mice. Thus, the phenotypic effect of the Hcs locus appears to be dependent on promotion of liver tumor induction by the male hormonal environment. In agreement with studies on the growth rate of the foci in male mice, the [3H]thymidine labeling index of G6Pase-deficient hepatocytes in C3H/HeJ males (12%) was 1.5-fold higher than in C57BL/6J male mice (8.0%) at 20 weeks and 1.2-fold higher at 28 weeks (11% versus 9.5%). The labeling index of histochemically normal hepatocytes in C3H/HeJ male mice (0.38%) was 2.6-fold higher than in C57BL/6J mice (0.15%) The Hcs locus may affect the promotion phase of hepatocarcinogenesis in male mice by increasing the proliferative rate of both normal and preneoplastic hepatocytes.