OBJECTIVES: We have previously demonstrated that full adherence with ACE-Inhibitors (ACEI) or statins in a post-myocardial infarction (MI) population is associated with lower rate of cardiovascular (CV) events compared to partial- or non-adherence. Herein, we sought to determine the direct medical costs attributable to partial- and non- adherence to these therapies. METHODS: Data on CV events and resource utilization were collected through a retrospective, nested cohort study in a large US insurer database.  We also analyzed two national files for physician and non-physician unit cost weighted averages of CV events (stroke, MI, atherosclerosis or angina), procedures (revascularization and CV tests) and visits (emergency room and outpatient CV visits).  We estimated per person cost differences between adherence groups and the sensitivity of the results using weighted and unweighted averages. A third-party payer economic perspective was adopted; all costs were expressed in 2014$. RESULTS: The estimated per patient weighted average annual cumulative medical costs were $5,153 for adherent, $6,470 for partially-adherent and $6,767 for non-adherent patients. This difference was mainly driven by a lower rate of CV events and revascularizations for adherent patients. Applying referenced unweighted averages, we estimated that the MI reference unit cost was $4,325 higher than the weighted average cost (p<0.001); the CV test unit cost was $1,010 higher than the weighted average cost (p=0.001). Using national prevalence data for incident MIs and medication adherence, we project that full adherence may lead to annual savings of $98.2 million and $100.9 million over partial- and non-adherence, respectively. CONCLUSIONS: Full adherence to statins and ACEI was associated with reduced per patient monthly direct medical costs of $109.7 and $134.4 over partial- and non-adherence.  Using unweighted, rather than weighted, averages overestimated the economic impact, indicating the importance of data type in such analyses. Full adherence to guideline-recommended therapies has tremendous cost-saving implications.