Combined antihypertensive therapy plays a crucial role in achieving targeted blood pressure reductions and renoprotection. We therefore compared the antihypertensive and antiproteinuric effects of combined therapy with either a calcium channel blocker (CCB) plus an angiotensin II receptor blocker (ARB) or an angiotensin converting enzyme inhibitor (ACE-I) plus an ARB in patients with type 2 diabetes mellitus complicated by overt nephropathy and mild to moderate hypertension. After a 12-week dietary control period, diabetic patients with mildly to moderately impaired renal function were randomly assigned to either a CCB (amlodipine 5 mg once daily) or an ACE-I (temocapril 2 mg once daily) for 12 weeks (monotherapy period). Both groups then received add-on therapy with an ARB (candesartan 4 mg once daily) for an additional 12 weeks. During the monotherapy period, blood pressure was decreased equally well in both groups. Daily urinary protein excretion remained unchanged in the CCB-treated group (control period, 4.0±1.8 g/day vs. CCB period, 4.1±1.9 g/day; ns; n =8), but decreased in the ACE-I-treated group (control period, 4.3±1.8 g/day vs. ACE-I period, 3.5±1.7 g/day; p <0.05; n =9). After the combined therapy period, blood pressure was decreased to the same degree in both groups. Although ARB plus CCB significantly reduced urinary protein excretion (to 3.5±1.5 g/day; p <0.05 vs. control period; n =8), a more profound reduction was achieved with ARB plus ACE-I (to 2.6±1.3 g/day; p <0.01 vs. control period; n =9). Monotherapy with the ACE-I increased the serum potassium concentration, and this elevation was sustained after addition of the ARB. In contrast, the serum potassium concentration was not influenced by monotherapy with the CCB, but was significantly increased after addition of the ARB. A decreased hematocrit was observed in the ARB plus ACE-I group. The present study suggests that combined antihypertensive therapy with either a CCB plus an ARB or an ACE-I plus an ARB exerts an antiproteinuric effect in patients with type 2 diabetic nephropathy with mildly impaired renal function. Although the latter combination had a more profound effect, it was associated with an increased serum potassium concentration and worsening of renal anemia. Thus, the combination of a CCB and an ARB should be the first line antihypertensive therapy in those with overt diabetic nephropathy. The long-term efficacy of these combined antihypertensive therapies will need to be further addressed in a future study. (Hypertens Res 2002; 25: 849-855)