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There is scarce information regarding ambulatory blood pressure (BP) achieved in daily practice with a wide range of antihypertensive drug combinations. We looked for differences in office and ambulatory BP among major drug combinations of two and three antihypertensive agents from a different drugs class. A total of 17187 patients treated with six types of two-drug combinations and 9724 treated with six types of three-drug combinations from the Spanish ABPM Registry were analyzed. We compared achieved office and ambulatory BP, as well as office (< 140/90 mmHg) and ambulatory (24-hour BP < 130/80; day BP < 135/85, and night BP < 120/70 mmHg) BP control among groups. The combination of renin-angiotensin system (RAS) blockers with diuretics and the triple combination of RAS blockers with diuretics and calcium channel blockers (CCB) were associated with lower values of 24-hour, daytime and nighttime BP, as well as more pronounced nocturnal BP dip. Compared with such combinations (reference), other double combinations had lower rates of ambulatory BP control. Moreover, triple combinations containing alpha blockers also had lower rates of ambulatory BP control. We conclude that even with similar office BP control, differences exist among antihypertensive two-drug and three-drug combinations with respect to ambulatory BP control achieved during treatment, with RAS blockers/diuretics and RAS blockers/CCBs/diuretics obtaining better control rates. This can help physicians choose among drug combinations in order to obtain further ambulatory BP reductions.