Hypercholesterolemia is a major risk factor for cardiovascular disease (CVD), the leading cause of death worldwide. Since the late 1980s, statins have emerged as effective lipid-lowering therapies and are now widely used to protect against and slow the progression of CVD and cerebrovascular disease. However, there is a significant gap between disease improvement in clinical trials and daily practice possibly attributable to poor adherence with statin therapy. High discontinuation rates were reported in primary and secondary prevention. This systematic review aims to summarize the current literature regarding the association between statin therapy discontinuation and cardiovascular and cerebrovascular events and all-cause mortality in high-risk patients. Available English literature was reviewed using Medline, Embase, Web of Sciences and the Cochrane Library; 39 studies were identified. In primary and secondary prevention, as well as perioperatively, non-adherence or discontinuation of statin therapy was associated with detrimental effects on cardiovascular and cerebrovascular outcomes, including disease severity and mortality. Importantly, some studies reported that very low adherence and discontinuation was associated with worse outcomes than never using statins. In conclusion, non-adherence and discontinuation of statin therapy significantly increased the incidence of cardiovascular and cerebrovascular events as well as all-cause mortality in high-risk patients. Patients would therefore benefit from closer adherence assessment and education programs aimed at increasing awareness of the risk associated with discontinuation of statin therapy.