The aim of this prospective, randomized, open-label, masked, endpoint, crossover study was to compare the antihypertensive efficacy of valsartan with that of losartan—angiotensin II (Ang II) receptor antagonists with different pharmacologic profiles—in patients with mild-to-moderate essential hypertension. After an initial 2-week placebo washout period, 40 patients (24 men and 16 women, aged 39 to 58 years) were assigned randomly to receive valsartan 80 mg or losartan 50 mg once daily for 4 weeks. After an intermediate 2-week placebo washout period, patients were switched to the alternative regimen for an additional 4 weeks. After the initial placebo washout period and every 2 weeks thereafter, 24-hour ambulatory blood pressure monitoring (ABPM) was performed using a noninvasive device, and casual blood pressure (BP) and heart rate were measured. Both losartan and valsartan had a clear-cut antihypertensive effect. However, valsartan showed significantly better antihypertensive efficacy compared with that of losartan, as demonstrated by (1) the 24-hour, daytime, and nighttime ABPM values, which were significantly lower (P < 0.01) with valsartan; (2) the percentage of abnormal BP readings, which was significantly lower with valsartan; (3) the trough/peak ratio and the smoothness index, which were both significantly greater with valsartan, suggesting a more homogeneous antihypertensive effect; and (4) the 24-hour postdosing clinic systolic and diastolic values, which were lower than those obtained with losartan. These findings underline the potential importance of the pharmacodynamic and pharmacokinetic differences in terms of antihypertensive efficacy for the different drugs belonging to the Ang II receptor antagonist class.