OBJECTIVES:  Control of hypertension (HTN) remains unsatisfactory in the majority of cases. The improvement of HTN control is the target of introducing multidrug, fixed-dosed combinations (FDC) of complementary drugs. The aim of this study is to compare the efficacy of FDC versus extemporaneous combinations (EXT) on total mortality and cardiovascular morbidity in a real-life setting. METHODS:  Longitudinal, retrospective, post-observational study in a Primary Care setting of the Comunidad Valenciana in Spain, that included 116,937 hypertensive patients treated with angiotensin 2 receptor blockers (ARB) and at least calcium channel blockers (CCB) or one diuretic (D), either on EXT or FDC, during the years 2012 and 2013. RESULTS:  The proportion of female gender was 53,2 %, mean age was 66,3 ± 13,2 years. 35% of patients kept FDC throughout the study, 34% maintained EXT, 4% added, 3% switched to FDC, 7% switched to EXT, 4% added EXT, 13% kept both. Both strategies reduced BP, but systolic and diastolic reductions were significantly larger in the FDC group (4,3 vs. 3,5 mmHg y 2,2 vs. 1,8 mmHg, p<0.0001), respectively, as was the proportion of controlled patients at follow-up (55,7 % vs. 55,3 %, p<0.001). Treatment with FDC was associated with a reduced total mortality (5,3 % vs. 8,4 %, OR: 0,88; CI 0,87/0,89; p<0.0001), a reduced incidence of stroke (3,8 % vs. 4,5 %, OR: 0,83; CI 0,79/0,87; p<0.0001) and of ischemic heart disease (4,9 % vs. 7,9 %, OR: 0,60; CI 0,58/0,63; p<0.0001) compared to extemporaneous treatment, not only in patients maintaining FDC during the whole study, but also in those who switched to or added FDC. CONCLUSIONS:  Higher reductions of BP, a higher proportion of controlled patients and a lower total mortality and cardiovascular morbidity are achieved with ARB in fixed-dosed combination with diuretics or calcium channel blockers in comparison with extemporaneous combinations.