OBJECTIVES: Pharmacological adherence plays an essential role in controlling hypercholesterolemia. Pharmacological care is also affected by the prescribing inappropriateness and adverse drug reactions (ADRs). ADRs can lead to a perceived lack of therapy effectiveness and subsequent suboptimal adherence. Our aim was to evaluate the impact of statin-induced, muscle-related ADRs on patients’ therapy adherence, and how this relationship may compromise the efficacy of physicians’ prescribing choices and health outcomes in clinical practice METHODS: A retrospective cohort study was performed using data from databases of 4 Local Health Units (LHUs) located in Emilia-Romagna, Toscana and Umbria regions, with an overall population of about 1.1 millions of inhabitants. All subjects aged≥18 years with a first prescription for statins in the period 01/01/2007-30/06/2008 were included. Baseline and follow-up LDL-C levels were considered RESULTS: A total of 71,855 patients (51% men, age 68.6±10.6) were included. Among them, 31,544 (43.9%) had ≥1 LDL-C values during the follow-up period: only 37.4% of these patients achieved LDL-C target. 23.6% of patients underwent ≥1 CPK measurement: out of range values were identified in 37.8% of them. Patients with steadily normal values of CPK showed a better medication-taking behavior compared to patients whose CPK values were out of normal range. Furthermore, a greater percentage of switching to other statin drug and/or dosage was observed in patients with out of range CPK levels compared to those with normal serum CPK levels CONCLUSIONS: Our findings indicate that physiological serum CPK levels were associated with greater adherence to statin therapy, supporting a causal link between non-adherence behavior and muscle-related ADRs occurrence. Since statin benefits are associated with their chronic use, physicians should be aware about the relevance of monitoring their patients for this harmful link to prevent unsuitable therapeutic decisions, further decreasing adherence, and achieve long-term health outcomes