In patients with insufficient blood pressure (BP) control, despite using a combination regimen containing an angiotensin receptor blocker and a calcium channel blocker (CCB), whether a greater dose of CCB or adding a diuretic is more effective at lowering BP remains unclear. We conducted a multicenter randomized clinical trial to compare the efficacy of switching from the daily administration of a single-pill fixed-dose combination of irbesartan (100 mg) and amlodipine (5 mg) to irbesartan (100 mg) with an increased dose of amlodipine (10 mg) (HD group, n=62) or irbesartan (100 mg) and amlodipine (5 mg) with 1 mg of indapamide (D group, n=63) in patients with poorly controlled hypertension. BP measured at home was monitored by a physician using a telemonitoring system. Between the HD and D groups, no significant differences were observed in morning home BP changes (mean reduction of systolic/diastolic BP, 1.7/0.9 mmHg; 95% confidence intervals, -2.4 to 5.7/-1.4 to 3.2; P=0.19/0.37), achievement rate of target BP (45.2% vs. 42.9%, P=0.80), BP variability independent of the mean (P⩾0.74), other variability indices (P⩾0.55) and time to stabilization, which was calculated using a fitted analysis (13.1 days vs. 11.4 days, P=0.99). Although a significant increase in serum uric acid was observed in the D group (P<0.0001), neither clinically relevant abnormal laboratory test results nor critical BP changes were observed throughout the trial period. Both antihypertensive drug combination strategies were effective treatment options. Further investigation is required to determine the appropriate use of both therapies based on the various pathologies associated with hypertension.