Abstract Background Previous clinical trials suggested that a strategy based on a cardiovascular (CV) polypill improves risk factor control and reduces the incidence of CV events. The CNIC-Polyill (aspirin (ASA) 100mg, atorvastatin 20/40mg (or simvastatin 40mg) and ramipril 2,5–10mg) has shown to improve adherence and risk factors control. Methods The NEPTUNO study is a retrospective, non-interventional analysis of an anonymized medical history dataset in the BIG-PAC administrative database in the years 2015–2018. Patients at age ≥18 years with previous CV disease were allocated in four different cohorts according to their therapy: CNIC-polypill containing ASA 100mg, R 2.5/5/10mg and A 20/40mg (1:case cohort), identical mono-components (ASA,R,A) (C2), equipotent medication (ASA 100mg, simvastatin 40/80mg or rosuvastatin 5/10mg, enalapril 5–20mg or valsartan 40–160mg) (C3) and usual care (C4) (control cohorts) and were followed for 2 years. To ensure comparability of the study cohorts, a propensity score matching (PSM) was performed. The primary endpoint was the incidence first major cardiovascular event (MACE) including: myocardial infarction, angina, ischemic stroke, transitory ischemic attack, peripheral artery disease and CV mortality. Results 8,946 patients were recruited. After the PSM, 4 well-balanced cohorts of 1,614 patients were obtained. The mean age was 63.3 years and 60.4% were men. Cohort 1 (Case cohort, CNIC-polypill) compared with cohorts 2, 3 and 4 showed a significant reduction in MACEs (19.8% vs. 23.3%, 25.5% and 26.8%; p<0.001), respectively although the CV death rate (8.1% vs. 8.1%, 8.9% and 9.2%; p=0.357) did not show differences. The hazard ratio (HR) for a MACE in the CV polypill cohort vs cohort 2 was 0.761 (IC95%; 0.657–0.881), p=0.001; vs Cohort 3 was 0.821 (IC95%; 0.714–0.944), p=0.006 and vs. Cohort 4 was 0.834 (IC95%; 0.716–0,950), p=0.008. Time to the event was also longer in the CV-polypill cohort compared the other 3 cohorts (274.8 days vs 249.2 days; 226.4 days and 217 days; p<0.001). There was a significant greater reduction in the case cohort vs the 3 control cohorts in the absolute levels of all the analyzed lipidic variables (LDL (−19.6 vs. −12.9, −12.3 and −9.1 mg/dL; p<0.001), triglycerides (−67.5 vs. −59.9, −56.1 and −54.4 mg/dL; p<0.001)) and in reduction of blood pressure (PAS (−14.1 vs. −11.7, −10.4 and −10.4 mmHg; p<0.001) and PAD (−4.5 vs −2.5, −2.1, −1.2 mmHg; p<0.001)). Higher persistence to treatment in the CNIC- polypill cohort (72.1% vs. 62. 2%, 60.0% and 54.2%; p<0.001) was also found. Conclusion This study shows the reduction of clinical events by the CNIC-polypill in a large population of real-life patients. In spite of the retrospective design of this study, the results of our analysis support the use of a CV-polypill in secondary prevention of cardiovascular events. These results need to be confirmed by prospective randomized clinical trials with major clinical outcomes. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): Ferrer International Figure 1