OBJECTIVES: To calculate the return-on-investment (ROI) for a medication therapy management (MTM) program. METHODS: Patients were included if they: i) started a MTM pilot program during Jul 1, 2014 to Sep 1, 2014, and ii) were continuously enrolled six months before and after their index date, defined as the date on which a patient started the MTM program. Using claims data from a commercial payer, mean and median healthcare utilization and cost in the six months before the index date were compared with that in the six months after the index date. A comparison group was randomly selected from eligible candidates for the MTM program who were not contacted. ROI was calculated in two ways: i) by taking the mean pre-post savings, or difference in costs in the six months before versus after the index date, and dividing by program costs, and ii) by taking the difference in pre-post savings between the intervention group and comparison group, and dividing by program costs. RESULTS: There were 75 patients in the intervention group and 99 patients in the comparison group. Using the first method, the ROI for the MTM program was calculated as approximately $2.50 savings for every $1 spent. Using the second method, the ROI for the MTM program was calculated as approximately $4 savings for every $1 spent. CONCLUSIONS: There are various methods in calculating ROI for MTM programs; one must be careful to understand the strengths and weaknesses of each method.