Unlike other dihydropyridine calcium channel blockers (CCBs), cilnidipine has been reported to exert an N-type calcium-channel-blocking activity and to reduce sympathetic hyperactivity. This study compared cilnidipine and amlodipine with respect to their effects on renal function and proteinuria. Twenty-eight proteinuric hypertensive outpatients (13 men and 15 women, aged 62+/-2 years) who had been maintained on CCBs for more than 3 months were randomly assigned to a group receiving amlodipine besilate (14 patients) or a group receiving cilnidipine (14 patients). CCBs were increased in dosage or other drugs were added until blood pressure decreased below 140/90 mmHg, but no inhibitors of the renin-angiotensin (RA) system were added or changed in dosage. Before and at 6 and 12 months after randomization, the concentrations of urine protein, urine albumin, serum and urine creatinine (Cr), and serum beta2-microglobulin were determined. The amlodipine group showed a significant increase in proteinuria, while the increase was suppressed in the cilnidipine group. The rate of increase in proteinuria at 12 months was 87% (95% confidence interval (CI) -10 to 184) of the baseline value with amlodipine and 4% (95% CI -69 to 77) of baseline with cilnidipine, a significant intergroup difference (p<0.05). The mean blood pressure remained in the 96-99 mmHg range until 12 months after randomization, showing no significant difference between the two groups. The cilnidipine group showed an increase in serum Cr levels (baseline vs. 12 months, 1.36+/-0.20 vs. 1.50+/-0.23 mg/dl, p<0.01). Overall, an inverse correlation existed between the changes in Cr and proteinuria (r= -0.477, p<0.01). These results suggest that cilnidipine results in a greater suppression of the increase in proteinuria and greater reduction in glomerular filtration rate than amlodipine, and that these effects are similar between cilnidipine and RA inhibitors. However, additional large-cohort and longer-term studies will be needed to clarify whether cilnidipine is superior to other CCBs in maintaining renal function.