Aims The purpose of this study was to investigate the risk of rhabdomyolysis in subjects initiating statin therapy for primary prevention of cardiovascular disease, focusing on the type of statin, dose and time since initiation. Methods and results A nationwide cohort study using French hospital discharge and claims databases was performed, studying subjects from the general population 40–75 years in 2009, with no history of cardiovascular disease and no lipid-lowering drugs during the preceding three-year period, followed for up to seven years. The primary outcome was hospitalization for rhabdomyolysis. Event-free survival analysis and case-time-control analysis were both performed, separately by gender. The cohort included 8,236,667 subjects, 969,460 of whom initiated a lipid-lowering drug for cardiovascular disease primary prevention. During 18,407,391 person-months exposed to statins, 168 events were observed, corresponding to an incidence of rhabdomyolysis of 1.10 per 10,000 person-years (1.54 in men vs 0.81 in women); 10/168 cases were fatal, and 18/168 and 57/168 cases occurred during the first month and first trimester of treatment, respectively. Survival analysis did not reveal any increased overall risk (hazard ratio = 1.02 (0.83–1.25) in men and 0.76 (0.60–0.96) in women). However, exposure to high-potency statins was associated with an increased risk in men (hazard ratio = 1.93 (1.27–2.94)). Rosuvastatin 20 mg (in men and women) and simvastatin 40 mg (in men) were associated with hazard ratios > 5. Case-time-control analyses showed similar patterns of risk. Drug interactions did not appear to significantly contribute to rhabdomyolysis events in this study. Conclusion Although the overall risk of statin-associated rhabdomyolysis in the context of primary prevention was not increased, the first months of treatment and the use of high-potency statins represent at-risk situations, which require appropriate monitoring, especially in men.