OBJECTIVES:  To estimate the potential impact of personalized clinical decision support (CDS) of statin therapy on achieving goal LDL-cholesterol (LDL-C) levels and the effect on atherosclerotic cardiovascular events (CVEs) and healthcare costs. METHODS:  A retrospective analysis of EHR data for 2.673 million commercially insured patients with elevated LDL-C who met AHA/ACC criteria for and were treated with statins. Evidence-based CDS recommended most effective/least effective statin drug-dose combinations to reach goal LDL-C for each individual. Likelihood of subsequent CVE for patients receiving recommended most effective/least effective drug-dose combinations were based on observed LDL-C and published medical research. Agent-based and Monte Carlo simulation were used to extrapolate CVEs and subsequent cost of care over a ten-year period for 20,000 treated patients. For 10,000 simulation runs, costs were calculated for payers and patients based on national averages for provider reimbursement and patient copayments and deductibles. RESULTS:  Wide variance in the efficacy of statin therapy strategies was observed. The proportion of patients achieving goal LDL-C levels ranged from 14% to 42%, median 31%, across 26 typical statin therapy drug-dose combinations. The reduction of LDL-C ranged from 59mg/dL (37%) to 12mg/dL (9%), median 23mg/dL (17%). Simulations of the most effective/least effective statin drug-dose combinations showed significant differences in ten year expected (a) number of CVEs (509 vs. 813), (b) total cost of care ($83 M vs. $99 M), and (c) patient out-of-pocket expenses ($26 M vs. $33 M). CONCLUSIONS:  Approaches to statin therapy are highly variable and associated with significant differences in outcomes and cost of care. Cardiovascular disease remains the single most common cause of morbidity and mortality in the U.S., and lower LDL-C levels are associated with reduced numbers of CVEs. Personalized, evidence-based clinical support guidelines can help practitioners identify the most clinically- and cost-effective pharmacological interventions.