Objective: Prior Latin American (LA) population-based studies have shown blood pressure (BP) control rates of 40%-50% in treated patients (population control rates: 16%–20%), which are far below the targets of the Pan American Health Organization (PAHO) for 2019. Fixed-dose combinations of antihypertensives have been associated with improved adherence, better patient convenience and higher efficacy, compared with separate agents and monotherapy. This study assessed the real-life effectiveness and safety of a fixed amlodipine/irbesartan (A/I) combination in the long-term management of hypertension (HTN) in LA.Design and method: This was a 48-week, prospective, observational, single-cohort study conducted in Argentina, Chile, Colombia, Guatemala, and Mexico. Adults with uncontrolled HTN, treated with A/I fixed combination per the treating physician's judgment, were followed in routine care. Target BP was defined as SBP/DBP < 140/90 mmHg (<130/80 mmHg for patients with diabetes or renal disease). Results: A total of 509 patients (57.6% females) were included with a mean (SD) age of 60.6 (12.5) years and a median Framingham 10-year risk score of 8.0%, 43.2% had comorbid dyslipidemia, and 24.8% were ever-smokers (5.9% current). Over 48 weeks, 97.4% of patients reported taking greater or equal 80% of prescribed doses. Statistically significant and clinically important improvements in SBP (−25.7 mmHg; p < 0.001) and DBP (−13.5 mmHg; p < 0.001) were observed. BP control was achieved by 62.7% of patients (99%CI: 57.5%–68.6%). In multivariate analysis, country of residence (p = 0.011), treatment compliance (OR = 6.9; p = 0.035), and diabetes presence (OR = 0.3; p < 0.001) were significant predictors of target BP. There were 124 Treatment Emergent Adverse Events (TEAEs) experienced by 89 (17.5%) patients, including 7 serious TEAEs by 5 (1.0%) patients. TEAEs were not related to A/I (76.6%). Conclusions: In real life, an A/I fixed combination was effective in long-term management of patients with HTN, with BP control rates close to the PAHO target despite significant regional variability. Treatment adherence was significantly associated with BP control