OBJECTIVES: To determine the relationship of polypharmacy on blood pressure (BP) control, compliance, persistence, the cost and incidence of cardiovascular events (CVD) in patients with moderate/severe hypertension. METHODS: An observational multicenter retrospective study. We evaluated patients > 30 years who started a third antihypertensive treatment during 2004-2006. Depending on the number of chronic medications, we established 3 groups: regular consumption of 3-6 drugs, between 7-10 and ≥11. Top measures: sociodemographic, comorbidity, BP, compliance and persistence. For each group we determined the incidence of new CVD and total costs. Patients were followed for 4 years. RESULTS: We evaluated 1,906 patients, 765 between 3-6 drugs, 624 between 7-10 and 517 in _ 11 (P <0.001). Overage age: 69.4 years and 55.5% women. The group of 3-6 drugs showed better BP control (51.8 vs. 47.0 and 41.1%, P <0.001), compliance (71.4 vs. 69.9 and 67.1%, P = 0.017), persistence (50.1 vs. 45.5 and 46.2%, P = 0.044) and lower incidence of CVD (12.2 vs. 19.7 and 30.2%, P <0.001), respectively. The average/unit total cost was 3,369.1 vs. 4,362.1 and s 4,902.3 (P <0.001). The presence of CVD was associated with therapy non-compliance (odds ratio [OR] 1.9, 95% confidence interval [95% CI] 1.1 to 3.6) and lower BP control (OR 1.4 [95% CI 1.1-2.0], P <0.05). The use of antihypertensive fixed dose has greater compliance (72.8 vs. 68.2%), persistence (64.4 vs. 39.3%) and degree of BP control (52.6 vs. 43, 8%), P <0.001. CONCLUSIONS: Polypharmacy is associated with lower compliance and persistence to antihypertensive treatment, cardiovascular disease and increased health care costs.