Background: Strategies to improve patients' tolerance of and adherence to statins may enhance the effectiveness of dyslipidemia treatment in those at risk for cardiovascular disease (CVD). Purpose: To assess the benefits and harms of interventions to improve statin adherence in patients at risk for CVD. Data Sources: MEDLINE, EMBASE, PubMed, and the Cochrane Library from December 2013 through May 2019 (English language only). Study Selection: Systematic reviews (SRs), randomized controlled trials (RCTs), and cohort studies that addressed interventions for improving statin tolerance and adherence. Data Extraction: One investigator abstracted data and assessed study quality, and a second investigator checked abstractions and assessments for accuracy. Data Synthesis: One SR, 1 RCT, and 4 cohort studies were included. The SR found that intensified patient care improved adherence and decreased levels of total serum cholesterol and low-density lipoprotein cholesterol (LDL-C) at 6 months or more of follow-up. Compared with statin treatment discontinuation, nondaily statin dosing lowered total cholesterol and LDL-C levels. One large cohort study suggested that more than 90% of patients who discontinued statin treatment could be rechallenged with the same or a different statin and be adherent 1 year after a statin-related adverse event led to discontinuation. Two small cohort studies reported that more than 90% of patients who were previously intolerant to statins and who had low baseline levels of vitamin D were able to adhere to statins 1 year after vitamin D supplementation. Limitation: This is a qualitative synthesis of new evidence with existing meta-analyses, and studies had several methodological shortcomings. Conclusion: Although the strength of evidence for most interventions was low or very low, intensified patient care and rechallenge with the same or a different statin (or a lower dose) seem to be favorable options for improving statin adherence.