We investigated the effects of 3 days treatment with acetazolamide 250 mg three times daily on kidney function in 8 Type 1 (insulin-dependent) diabetic patients with nephropathy, and in 7 healthy subjects in a double-blind placebo controlled cross-over study. Glomerular filtration rate and extracellular fluid volume were measured with the single injection 51Cr-EDTA technique and fluid flow rate from the proximal tubules was determined by measurement of the renal lithium clearance. A 24% decline in glomerular filtration rate was observed in both groups during acetazolamide treatment (control subjects: 108±11 vs 82±9 ml/min, p<0.02, diabetic patients: 71±19 vs 54±14 ml/min, p<0.01). The renal lithium clearance (ml/min) remained about the same (control subjects: 22±6 vs 27±8, NS, diabetic patients: 14±5 vs 15±4, NS). Absolute proximal tubular reabsorption of water (ml/min) was reduced by about one-third (control subjects: 85±11 vs 56±7, p<0.02, diabetic patients: 55±17 vs 37±6, p<0.02), and fractional proximal reabsorption of water and sodium (%) declined (control subjects: 79±5 vs 67±8, p<0.02, diabetic patients: 79±5 vs 72±6, p<0.02). Renal sodium clearance and distal fractional reabsorption of sodium was unchanged. Extracellular fluid volume declined by 10% in both groups (p<0.02). Albuminuria and fractional albumin clearance decreased significantly in the nephropathic patients (p<0.02). Our study suggests that the effects of acetazolamide on kidney function are similar in healthy subjects and patients with diabetic nephropathy.