In order to analyze the genetics of susceptibility to promotion of hepatocarcinogenesis in DBA/2NCr and C57BL/6NCr mice by phenobarbital (PB), reciprocal F1 hybrid male mice were given 90 mg N-nitrosodiethylamine (NDEA)/kg body weight, i.p. at 5 weeks of age followed by 0.05% PB in drinking water. Hepatocellular adenomas and carcinomas were comparably increased in incidence and multiplicity in both reciprocal hybrids over mice given NDEA alone. Eight of 10 D2B6F1 progeny of DBA/2NCr females mated with C57BL/6NCr males, but only 1/10 B6D2F1 mice (progeny of C57BL/6NCr females mated with DBA/2NCr males) given PB after NDEA initiation developed single or multiple hepatoblastomas within 42 weeks. These small-celled, intensely basophilic tumors were characteristically hemorrhagic and highly malignant. Hepatoblastomas were mostly found within or adjacent to hepatocellular tumors. No hepatoblastomas were seen in either hybrid given NDEA alone. PB consistently enhanced development of malignant hepatoblastomas, as well as promoted hepatocarcinogenesis in D2B6F1 males, but did not elicit hepatoblastoma development in B6D2F1 males that were genetically identical to D2B6F1 males except for the reverse origin of their X and Y chromosomes.