The effect of continuous week-long administration of N-nitroso(2-hydroxypropyl)(2-oxopropyl)amine (HPOP) by s.c. implanted osmotic pumps was examined in male and female Syrian hamsters given access to three isocaloric synthetic diets containing 10 (LP), 20 (MP) and 30% (HP) casein respectively. At a total dose of 210 mg/kg, toxicity of HPOP, expressed as acute liver injury, was greater in male than in female hamsters. Such toxicity increased with protein intake in male, but not in female animals. Twenty-five weeks after initiation, female and male hamsters developed pancreatic ductal adenocarcinomas and to a lesser degree liver cholangiocellular and hepatocellular carcinomas. The highest incidence of pancreatic cancer was observed under HP diet regimens and was 75 and 67% in female and male hamsters respectively. Decrease of protein intake resulted in the reduction of the incidence of pancreatic cancer, which was more striking in males than in females. In males fed the MP and LP diets respectively, such an incidence declined to 33 and 6%. Although significant differences in the incidence of pancreatic cancer were not observed among female groups fed the above three diets, the multiplicity and the number of such tumors were significantly greater at the HP than the LP level. Differences in the incidence of pancreatic tumors between males and females were statistically significant only at the LP level. However, such differences were also significant at the MP level when comparisons were based on tumor number and multiplicity. Since the incidence, tumor multiplicity and size were generally greater in female than male hamsters, estrogenic hormones may play a role in the development of pancreatic ductal adenocarcinomas in this species.