Recent evidence suggests a role for lipid deposition in the pathogenesis of some forms of glomerular disease. To gain further insight into this phenomenon guinea pigs (GP) were fed a 2% cholesterol (HC) diet and compared to GP on a normal diet (C). Serial observations were made 5, 10, 30 and 70 days after the initiation of the experiment. HC gained less weight than C (P less than 0.001) and developed hemolytic anemia after 30 days. At all time periods serum total cholesterol (TC) was significantly elevated in HC (P less than 0.001). High density lipoprotein-cholesterol and total phospholipids (PL) were significantly higher in HC at days 30 and 70. Lipoprotein-X was detected in HC serum. The relative proportion (%) of cholesteryl ester (CE) at day 70 was significantly higher in HC than in C when renal cortical lipids were analyzed (P less than 0.017). Renal function was normal in both groups throughout the 70 days. The HC group developed proteinuria and hematuria (proteinuria, HC = 22.1 +/- 7.2 mg/24 hr; C, 6.4 +/- 2.3 mg/24 hr), which was detected at day 70 but not at day 30. HC developed significant progressive mesangial expansion which was first evident at day 30. In HC only oil red 0 material was first detected in glomeruli at day 5 and was very conspicuous at day 70. Increased intraglomerular monocyte numbers were detected at day 70 (P less than 0.017) but not at day 30 in HC. No glomerulosclerosis was observed in GP's with drug-induced hemolysis on a normal diet. To see the effect of high protein intake on HC GP's, a group of GP's was put on a HC diet for 30 days followed by a 2% cholesterol-high protein (HCHP) diet for 40 days. Compared to HC GP's, the HCHP group showed significantly higher serum TC and PL (P less than 0.017), mesangial expansion (P less than 0.01) and proteinuria (P less than 0.01). The results indicate that hypercholesterolemia plays an important role in the pathogenesis of glomerulosclerosis in this model and that the process appears to be mediated, at least in part in the later stages, by monocytes. The addition of protein to the HC diet augments these effects.