OBJECTIVES Drug-related adverse events impose a substantial burden on patients and health care systems. Electronic prescribing (e-prescribing) systems have been identified as effective tools to improve quality, safety, and efficiency in health care delivery. The purpose of this study is to evaluate the effectiveness of a wireless medication management program in a commercially available e-prescribing system in the prevention of serious drug-drug interactions (DDIs). METHODS This study employed a retrospective pre-post with a control group design to evaluate the effectiveness of wireless handled medication management program in preventing serious DDIs. A total of 1975 prescribers who received personal digital assistants (PDA) between August 1, 2004 and June 30, 2005 constituted the technology user group. The comparison group included 1063 prescribers who sent a request to obtain, but did not receive, the technology during the same period. Multivariate regression analysis was used to determine if there were differences between the two groups of prescribers in the rate of prescribing clinically important DDIs. RESULTS Prescribers in the two groups were significantly different in their specialty practice areas and number of pharmacy claims and at baseline. However both groups were similar in their average age, profession, and practice type. Prescribers varied in their use of the e-prescribing system to access patient medication history, the average number of patient medication history updates requested per prescriber in the user group was 42.09 (ranging from 0 to 1073). The most widely prescribed DDIs included those involving warfarin with non steroidal anti-inflammatory drugs (NSAIDs) and anticoagulants with thyroid hormones. Compared to the control group, PDA users did not have significantly greater decrease in the number of serious potential DDIs as compared to non users (p=0.65). CONCLUSIONS The availability of near real-time patient medication history did not have a significant impact on reducing the rate of prescribing clinically important DDIs.