Objective: Medicare beneficiaries have unique health-related challenges causing significant impact on quality of life. This study examined the overall health-related quality of life (HRQOL) and differences in HRQOL between subgroups of an ambulatory Medicare beneficiary population. Methods: Nine outreach events were held during the 2011 Medicare Part D prescription drug open-enrollment period, in which 397 beneficiaries were assisted with Part D plan evaluation and comprehensive medication therapy review. Demographic data were collected, and the SF-36v2 was administered to measure beneficiaries' self-reported HRQOL. Correlations were assessed between the mental component summary (MCS) or physical component summary (PCS) scores of the SF-36v2, prescription utilization, number of chronic conditions, and whether beneficiaries were government subsidyrecipients. Results: Mean Å standard deviation of PCS and MCS scores were 43.3 Å 11.4 and 52.2 Å 11.7, respectively. Both PCS and MCS scores were negatively correlated with the number of prescription medications and number of self-reported chronic conditions. Both PCS and MCS scores related to sociodemographics were significantly lower (P < 0.05) in subsidy and least-educated recipients. Conclusions: HRQOL can vary widely as a result of sociodemographic, drug, or disease differences in an ambulatory Medicare beneficiary population.