Objective: Drug-drug interactions (DDI) have been well associated with significant medical, safety, and economic consequences, particularly in older and chronically ill patients. This study examined several aspects of medication safety by quantifying and profiling the prevalence, population exposure, and characteristics of clinically significant DDIs among Medicare Part D utilizing beneficiaries. Lumetra and six California Medicare Advantage prescription drug plans (MAPD) and stand-alone prescription drug plans (PDP) will collaboratively utilize results to design effective quality improvement initiatives to minimize adverse clinical outcomes due to these DDI's. Methods: This study assessed the prevalence and population exposure of DDIs among Medicare and dual eligible (i.e., Medicare +Medi-caid status) beneficiaries enrolled across six of California's Part D MAPD and PDPs. Retrospective, cross sectional pharmacy claims data from January 1, 2006 through December 31, 2006 were analyzed to obtain the frequency of drug interactions that are clinically significant and well-documented in the medical and pharmacy literature. Results: The analysis included 368,607 utilizing beneficiaries. The overall prevalence rate of DDI was 5.9%. The number of clinically significant DDI cases was 7,962 per 100,000 beneficiaries. Stratified analyses indicated that males and older beneficiaries appear to be at a higher risk of incurring a clinically significant DDI. Risk of a DDI also increased as the number of unique medications and/or number of prescribing physicians increased per enrollee. Conclusion: The prevalence and characteristics of clinically significant DDIs among California elderly and chronically ill patients were positively associated with certain demographic factors and health care resource utilization profiles. Stratifying high-risk individuals with discrete or multiple DDI's will enable Part D MAPDs and PDPs to perform in-depth case management in targeted individuals. Point-of-service edits and information obtained from retrospective drug claims review can be used in conjunction to customize meaningful intervention strategies.