OBJECTIVES: To determine the cost-effectiveness (CE) of managing patient low density lipoprotein-cholesterol (LDL-C) levels with exercise plus nutritional therapy and exercise plus nutritional plus pharmacotherapy from the Indian Health Service perspective. METHODS: A retrospective database analysis was performed on data collected from a pharmacist managed Cardiovascular Risk Reduction Program (CVCRRP) from March 1997 through October 1999. Patients received exercise plus nutritional therapy (Group 1) or exercise plus nutritional plus pharmacotherapy (Group 2). Effectiveness measures included unit and percent LDL-C reduction from initial to last recorded visit. Costs (fixed plus variable) and reimbursements were determined in terms of 1999 dollar values through clinic staff interviews and billing records analysis. Average and incremental cost-effectiveness ratios (ICE) were calculated. One-way sensitivity analyses were performed varying pharmacist salary, medication costs, and levels of reimbursement. RESULTS: Net cost-per-patient in Group 1 (n=40) was $1,204; in Group 2 (n=32) was $1,432. Mean LDL-C reduction was 12.67mg/dl (Group 1) and 42.03mg/dl (Group 2). Mean percent LDL-C reduction was 8.95% (Group 1) and 50.70% (Group 2). Average CE ratios were $95.01 (unit LDL-C reduction) and $134.50 (percent LDL-C reduction) for Group 1; $34.07 (unit LDL-C reduction) and $50.70 (percent LDL-C reduction) for Group 2. ICE ratios for Group 2 versus Group 1 was $7.77 (unit LDL-C reduction) and $11.82 (percent LDL-C reduction). The obtained CE ratios were robust to sensitivity analysis parameters. CONCLUSIONS: The CVCRRP showed positive lipid management results for enrolled patients. Group 2 (those including pharmacotherapy) interventions were associated with higher costs and better LDL-C outcomes. Group 2 interventions also resulted in more favorable average CE ratios compared to Group 1. Study results could be used to develop similar cardiovascular risk reduction programs, expanding the clinical role of the pharmacist and improving patient outcomes.