Abstract Background Effective strategies for hypertension management are essential to reduce associated morbidity and mortality in sub-Saharan Africa, where blood pressure control rates are alarmingly low. Renin-angiotensin-aldosterone system (RAAS) inhibitors are recommended as first-line treatment; however, differences in class or molecule-specific effects have not been conclusively demonstrated. Purpose This real-world study analysed medical insurance claims data to assess clinical and cost outcomes of antihypertensive therapy based on the three most commonly prescribed RAAS inhibitors in South Africa: perindopril, losartan and enalapril. Methods Patients on standard doses of perindopril, enalapril or losartan (alone or in combination with other agents) for ≥12 months prior to January 2015 were identified from a large, South African private health insurance database. Anonymised patient-level claims over the next 5 years (January 2015 to December 2019) were analysed in patients with ≥80% adherence. The primary outcome was the risk-adjusted rate of the composite of myocardial infarction (MI), ischaemic heart disease (IHD), heart failure (HF) or stroke. The key secondary clinical outcome was the risk-adjusted all-cause mortality rate; risk-adjusted costs per life per month (PLPM) in South African Rands (ZAR) were also assessed. Results In total, 63,489 patients who received perindopril (n=32,857), losartan (n=16,693) or enalapril (n=13,939) were included. Within the 5-year study period, the risk-adjusted rate of ≥1 claim for MI, IHD, HF or stroke (primary outcome) was significantly lower with perindopril than losartan (205 vs 221 per 1000 patients; P<0.0001) or enalapril (205 vs 223 per 1000 patients; P<0.0001). The risk-adjusted all-cause mortality rate was also significantly lower with perindopril than enalapril (100 vs 139 deaths per 1000 patients; P=0.007), but similar to that with losartan (100 vs 94 deaths per 1000 patients; P=0.650). Perindopril was also associated with significantly lower overall risk-adjusted costs than the other agents, with mean (95% confidence interval) costs PLPM of ZAR 1342 (87–8973) for perindopril, ZAR 1466 (104–9365) for losartan (P=0.0044) and ZAR 1540 (77–10,546) for enalapril (P=0.0003). Conclusion In this real-world analysis of South African individuals with hypertension, perindopril-based regimens were associated with a lower rate of cardiovascular events (MI, IHD, HF and stroke) over 5 years than enalapril- or losartan-based regimens. Perindopril also provided considerably greater cost-saving benefits, both statistically and socioeconomically, compared with the other RAAS inhibitor agents. Although these observations need to be confirmed in a broader South African population, including those treated in the public health sector, they may have significant implications for the choice of antihypertensive therapy.Time to outcome event over 5 yearsRisk-adjusted cost in South African Rand