In previous studies we have shown that male rats carrying genes controlling growth and reproduction (grc) linked to the major histocompatibility complex (MHC) to be more susceptible to N-2-acetylaminofluorene than rats without grc genes. In the present studies we show that by manipulation of the diet of grc rats, hepatocarcinogenesis induced by another carcinogen can be altered. Male rats with the grc gene (R16) and wild type (ACP) were initiated with diethylnitrosamine (DEN) (200 mg/kg body weight). Some were fed laboratory chow (LC) for 9 months; others were fed a choline-supplemented (CS) or a choline-deficient (CD) diet. The rats were killed at various time periods and the liver sections were stained with H&E and for gamma-glutamyltranspeptidase (GGT). After 9 months on LC, the livers of R16 showed greater size and number of GGT-positive foci, bile duct proliferation, cellular atypia, cirrhosis, and nodular hyperplasia than the ACP. While the first hepatocellular carcinoma in R16 fed either a CS or LC was seen at 9-10 months, one R16 rat fed a CD diet had liver cancer at 4 months. On a CS diet the R16 showed greater GGT-positive foci at 2 months than the ACP. On a CD diet the R16 showed even greater size and number of GGT-positive foci. At 12 months, 15 of 22 (68%) of the R16 rats on a CD diet had liver cancer and seven of 24 (29%) of the R16 on a CS diet. Of the ACP, none of 15 (0%) on CS and one of 18 (6%) on CD diet had liver tumors. The results show that the grc genes confer high susceptibility to liver cancer, which is enhanced by a CD diet, suggesting synergism between genetics and diet.