The influence of interactions between dietary fat and protein on spontaneous diseases was investigated in Syrian golden hamsters fed two levels of corn oil [4.5 or 18 g/385 kilocalories (kcal)] with each of two levels of casein (9 or 36 g/385 kcal). The four diets were fed to separate groups in two different sequences: 1) Diets were given during weeks 3-7 and followed by control diet (9 g corn oil and 18 g casein/385 kcal), or 2) control diet was fed during weeks 3-7, and the four diets were fed from week 8 until death. Dietary interactions of fat and protein modified spontaneous degenerative, inflammatory, and proliferative diseases in hamsters. For example, amyloidosis in the liver, kidneys, spleen, and adrenal glands was reduced in females by feeding high-fat-high-protein (HF-HP) diet in comparison with low-fat-high-protein (LF-HP) diet during weeks 3-7 or by feeding LP diets at either fat level after 8 weeks. The incidence of hepatic abscess was highest in males consuming HP diet at either fat level after 8 weeks, and hepatic necrosis was observed most often in hamsters fed HF-HP diet after 8 weeks. Gastric and renal vascular calcification and nephrocalcinosis incidences were reduced by 50-100% in hamsters fed HF-HP diet after 8 weeks, and HF diet fed at this time reduced vascular calcification in the heart in both sexes and in the lungs in males. Inflammation was generally influenced similarly by diets fed either during weeks 3-7 or after 8 weeks. In the prostate gland, inflammation was observed most frequently in males fed HF-LP diet; however, in the vagina inflammation was elevated in females fed HF-HP diet and found in the gallbladder more commonly in hamsters fed HF-HP than in those given LF-HP. The incidence of colitis was decreased by giving HF-LP diet during weeks 3-7 or LF-LP diets after week 8. The incidence of gastric ulcer was high in males fed HF diets during weeks 3-7, and intestinal ulcers were high in those fed LF-LP at this time. The adrenal hyperplasia incidence was highest in males given HF-HP diet before or after 8 weeks and in females given this diet after 8 weeks. Similarly, ovarian and hepatic ductal hyperplasia was highest in females fed HF-HP diet after 8 weeks, and gastric and intestinal hyperplasia increased with the rise in fat at both protein levels in both sexes.(ABSTRACT TRUNCATED AT 400 WORDS)