This double-blind, active- and randomized-controlled study compared the efficacy and safety of a fixed-dose combination of valsartan/hydrochlorothiazide 80 mg/12.5 mg once daily (n = 32) with amlodipine monotherapy 5 mg once daily (n = 33) for 8 weeks in patients with mild to moderate hypertension. Non-inferiority of valsartan/hydrochlorothiazide to amlodipine was demonstrated by comparable reductions in sitting systolic blood pressure (SBP), sitting diastolic blood pressure (DBP), and daytime, night-time and 24-h SBP and DBP on ambulatory blood pressure monitoring. Between-group comparisons of adverse events and changes in laboratory parameters did not reach statistical significance, except for uric acid which showed a significant increase in the valsartan/hydrochlorothiazide group compared with the amlodipine group, but was still below the laboratory's upper limit of normal. In conclusion, the use of the fixed-dose combination of valsartan/hydrochlorothiazide 80 mg/12.5 mg once daily as a starting regimen in patients with mild to moderate hypertension was shown to have non-inferior efficacy and comparable safety for daily practice compared with amlodipine 5 mg once daily monotherapy.