The development of focal segmental glomerular sclerosis (FSGS) and its relation to hypertriglycemia were studied in unilateral nephrectomized rats. Group A (n = 6), fed standard rat chow supplemented with 20% beef tallow and 0.6% cholic acid for 25 weeks, showed evidence of hypertriglycemia (109.4 +/- 4.3 mg/dl). Group B (n = 7) was given the same rat chow as group A, but they did not have high serum levels of TG (66.4 +/- 2.3 mg/dl). Group C (n = 6) were the controls and their serum TG levels were 53.0 +/- 3.8 mg/dl. The incidence of FSGS and body weight was significantly higher in group A than in groups B (p less than 0.01) and C (p less than 0.05). In all three groups, rats with over a 4% FSGS revealed significantly high serum TG levels, proteinuria, and body weight, as compared with rats with less than 1% of FSGS. The serum cholesterol levels did not correlate with the incidence of FSGS. We tentatively conclude that hypertriglycemia induced by a diet rich in saturated fatty acid may play an important role in the production and progression of FSGS.