Background and purpose: The aim of the study was to provide valuable real-world long-term safety data of the fixed pravastatin 40 mg/fenofibrate 160 mg combination in comparison of monotherapy with statins of moderate intensity. Materials and methods: POSE study was an observational, comparative study conducted in three European countries. Patients treated or planned to be treated with pravastatin 40 mg/fenofibrate 160 mg or with a moderate-intensity statin in monotherapy were assessed over 3 years. The main safety endpoints included the incidence of renal or urinary disorder, musculoskeletal or connective tissue disorder, hepatobiliary disorder and cardiovascular events. Results: The study included 3075 patients treated for dyslipidemia, with diabetes mellitus (47%), hypertension (56%) and/or established cardiovascular disease (61%). Over the three years of follow-up, the incidence of each safety event was low (≤3%) and similar in both treatment groups. The most frequently occurring events were; musculoskeletal and connective tissue disorders (44 events in the pravastatin 40 mg/fenofibrate 160 mg group and 36 in the statin group), renal and urinary disorders (28 versus 24), and aggravated diabetes mellitus (31 versus 21). Most events occurred during the first year, then incidence decreased over the three-year period. The incidence of cardiovascular events was low in both groups (≤1.6%), with no new signal emerged from the long-term follow-up. Conclusions: This study demonstrates a reassuring long-term safety profile of the fixed pravastatin 40 mg/fenofibrate 160 mg combination in routine clinical practice, with low and similar incidence of events over the three years follow-up compared to a monotherapy with statins of moderate intensity.