Background: In 2006. the Center for Medicare & Medicaid Services incorporated the requirement for a Medication Therapy Management Program (MTMP) for individuals with Part D coverage to ensure that drug regimens provide optimal therapeutic outcomes through improved medication use, thereby reducing adverse drug events. Objective: To evaluate the effectiveness of an MTMP implemented for Medicare Advantage Prescription Drug members enrolled with Health Alliance Plan (HAP) during 2006 and 2007. Methods: Patient eligibility for MTMP was searched electronically. Clinical pharmacists researched medication histories and adherence and, through telephone contact, ascertained the patients' healthcare goals and needs. A patient-centered pharmacotherapy plan was created and implemented collaboratively with the patient's physician(s). To ensure that therapy goals were met, pharmacists performed follow-up interventions. Clinical outcomes and cost savings were compared for MTMP enrollees versus those declining enrollment. Results: Average enrollment rate for the MTMP was 20% for 2006 and 2007. Nearly 60% of interventions involved changing therapy to improve efficacy and greater than 40% involved changing therapy to improve safety. Analysis of 2006 data revealed an overall improvement in electronically measurable clinical outcomes for MTMP enrollees versus individuals who declined enrollment, including a trend toward improved adherence to drug therapy for heart failure, insulin use, and a significant reduction in gastrointestinal bleeds (p = 0.001). Cost-savings analysis indicated a greater reduction in total prescription per member per month costs ($PMPM) of 17.2% for MTMP enrollees versus a 7% reduction for those who declined MTMP (p = 0.001). Patients who enrolled into the 2006 MTMP also saw a sustained positive effect in lowered $PMPM for prescription drugs in 2007. Conclusions: The HAP MTMP, conducted through telephone contacts, produced positive trends in improving clinical outcomes, reductions in pharmacy costs, and sustained pharmacy cost savings for patients who enrolled in the MTMP compared with patients who declined enrollment.