OBJECTIVES: To examine changes in the utilization of prescription medicines from 16 therapeutic classes from 2005 to 2006 attributable to the institution of Medicare Part D, a national prescription drug benefit program for the elderly instituted at the end of 2005 in the United States. METHODS: We implemented retrospective analyses of pharmacy claims of beneficiaries aged 67-79 years from 2005 to 2006, from a large pharmacy chain in the United States. Subjects aged 61-63 were used a control group in a differences-in-differences approach to account for trends not related to Part D. The final sample represented approximately 2.4 million unique beneficiaries aged 67-79. The main outcomes are: 1) Changes in proportion of total days of therapy dispensed as generics, and 2) changes in prescription utilization for each therapeutic class. RESULTS: Prescription drug use by these beneficiaries increased by 11% from 2005 to 2006. After adjustment for secular trends and other potential confounders, utilization of each therapeutic class was similar in 2005 and 2006. Small increases in drug utilization occurred for several drug classes, ranging from 0.66 pill days (0.46%) for users of nonsteroidal anti-inflammatories (NSAIDs) to 4.64 pill days (1.78%) for users of angiotensin-converting enzyme (ACE) inhibitors. Decreases occurred for anti-diabetic drugs (-2.06 pill days, -0.58%), beta-blockers (-1.24, -0.49%), and benzodiazepines (-5.96 pill days, -3.57%). Overall, beneficiaries were slightly less likely to fill prescriptions for generic drugs vs. brand-name drugs in 2006 compared to 2005 (OR 0.98, 95% CI 0.97-0.98). CONCLUSION: Small increases in prescription drug utilization occurred across numerous drug classes for these Medicare seniors following the implementation of the Medicare Part D Prescription Benefit, while overall market share by drug class did not change significantly. Further analyses are needed to explore the degree to which these changes reflect moral hazard versus beneficial expansions of coverage.