The concepts that increased intracellular Ca<sup>2+</sup> content and increased glomerular capillary pressure play an important role in the progression of chronic renal diseases has led to the suggestion that treatment with calcium-blocking agents (diltiazem; CBB) or converting enzyme inhibitors (captopril; CEI) may be indicated to prevent renal failure. We studied the effects of CCB and CEI on the early course of adriamycin (ADR) nephropathy, where glomerular pressure has been shown to be unchanged, blood pressure was only mildly elevated and renal failure incipient. Animals were studied 2,7,12,16 and 20 weeks after the second injection of ADR, 2 mg/kg. In treated rats, blood pressure remained normal. At the end of the study, proteinuria and serum creatinine were lower in ADR-CEI than in ADR rats (149 ± 42 vs. 616 ± 90 mg/day, p < 0.01 and 0.36 ± 0.04 vs. 0.58 ± 0.02 mg%, p < 0.01, respectively). ADR-CCB had values similar to those of untreated ADR rats. Mesangial expansion and focal glomerulosclerosis were present only in ADR and ADR-CCB rats, whereas in ADR-CEI rats the glomeruli were virtually normal. Glomerular <sup>45</sup>Ca uptake was increased in ADR, decreased in ADR-CCB rats, and normal in ADR-CEI. Glomerular 6-keto PGF<sub>1α</sub> and TxB<sub>2</sub> were significantly increased in ADR rats, and both treatments decreased TxB<sub>2</sub>. The results suggest that endogenous angiotensin II is important for the early progression of glomerular injury toward renal insufficiency, while tissue Ca<sup>2+</sup> accumulation may play an important role in more advanced phases.