Cardiovascular disease (CVD) is a major cause of mortality in the United States, representing the highest total expenditures among major diseases. To improve CVD-associated outcomes, medication therapy management (MTM) services have been included in essential health benefit packages offered by various health plans. Nevertheless, the impact of such MTM services on outcomes is still unclear, especially from the perspective of the self-insured employer. To (a) compare economic outcomes between patients who received and those who did not receive MTM services from the self-insured employer's perspective and (b) compare clinical outcomes before and after receiving MTM services. This study consisted of 2 pre- and post-retrospective designs: (1) a cohort study with comparison groups and (2) a cohort study within group comparison. Patients were beneficiaries aged 19 years or older who were diagnosed with CVD conditions according to ICD-9-CM codes and continuously enrolled in a public university-sponsored insurance plan between 2008-2010. Patients were divided into MTM and non-MTM groups. The first MTM encounter was assigned as the index date for the MTM group. Match-paired patients who did not receive MTM services were randomly assigned the index date based on age category, gender, and comorbidity. Measures for pharmacy, medical, and total expenditures were obtained from medical and pharmacy claims. Paired t-tests and independent t-tests using data generated from 1000 bootstraps compared mean cost difference within and between groups. The return on investment (ROI) was calculated by dividing the average net benefit from MTM services by the average cost of MTM services. Clinical parameters, including blood pressure (BP) and body mass index (BMI), were retrieved from electronic medical records from a pharmacist-provided clinic where MTM services took place. Paired-t tests were used to compare the mean difference between baseline and endpoint values. Further, this study examined changes in the proportion of patients who achieved an individualized treatment goal for BP and BMI. The study also quantified the improvement in disease stages after the index date using the McNemar's test. Statistical analyses were performed by using SAS software version 9.2 with statistical significance level of 0.05. A total of 63 patients and 62 match-paired patients were included in the MTM group and the non-MTM group, respectively. The mean cost (SD) per patient in the MTM group during the 6 months post-index period for CVD-related pharmacy, all-cause medical, and total expenditures was lower than the 6 months pre-index period by $22.0 (19.1), $79.2 (99.6), and $75.1 (136.2), respectively. In contrast, the mean cost (SD) for the non-MTM group increased during the 6 months post-index date by $10.7 (24.2), $246.4 (248.4), and $289.0 (269.5) for pharmacy, medical, and total expenditure, respectively. When comparing the 2 groups, the MTM group had statistically significantly lower costs per patient for pharmacy expenditures (difference of -31.9 ± 25.1, P less than 0.0001), medical expenditures (difference of -$325.6 ± 271.2, P less than 0.0001), and total direct expenditures (difference of -$359.3 ± 219.2, P less than 0.0001). Given the net benefit of MTM services ($359.3) and the average cost of MTM service ($134.6), the ROI was $1.67 per $1 in MTM cost. Regarding clinical outcomes, while no statistically significant differences were observed in clinical outcomes, MTM services demonstrated clinical benefits. At the post-index period, the percentage of patients who had achieved their goals increased from 55% to 70% for BP and from 13.0% to 21.7% for normal BMI compared with the pre-index period. In terms of the extent of improvement in disease stages, clinical improvements in the stages of hypertension (χ2 =12.77, P less than 0.05) as well as BMI (χ2 =6.39, P less than 0.05) at the endpoint were observed. Cardiovascular-related pharmacy, all-cause medical, and total expenditures were statistically lower among beneficiaries who received MTM services compared with those who did not. In addition, MTM services had a positive ROI and demonstrated clinical significances by the increasing number of patients who achieved treatment goals and improved disease stages for hypertension and BMI.