OBJECTIVES: The study objective was to examine the prevalence and factors associated with potential drug-drug interactions on ACE Inhibitors prescription in the U.S. from 2001-2004. METHODS: This project proposed a secondary data analysis using the U.S. National Ambulatory Medical Care Survey (NAMCS) conducted by the National Center for Health Statistics. A series of population weighted descriptive analyses were performed to evaluate the prevalence of potential drug interactions. Eisenberg's sociologic theory was adopted to identify the potential patient and physician's characteristics associated with the presence of drug interactions. A weighted multivariate logistic regression model was used to examine the significance of these predictor variables with 0.05 alpha level. RESULTS: From 2001 to 2004, there were 125.6 million visits where ACE inhibitors were prescribed for the treatment of hypertension in the U.S., 48.1 million (38.3%) of these visits encountered potential drug interactions. Significant patient characteristic included sex (OR=1.57), pay type (OR=<0.001), region (OR=2.41), age (P <0.001), and number of medications taken (P<0.001). Significant physician characteristics included metropolitan region (OR=0.22), office setting (OR=<0.001), physician employment (OR=<0.001), practice ownership (OR=<0.001), e-mail consultation (OR= 5.79), payment sources (OR=<0.001), and specialty; pediatrics (OR=139.61), cardiology (OR=61.30), dermatology (OR=<0.001), urology (<0.001), and otolaryngology (OR=<0.001). CONCLUSION: The study reveals a very high prevalence rate (38.3%) and recognizes various patient and physician's characteristics associated with potential drug interactions with ACE Inhibitors. From the public safety viewpoint, it is imperative for the interdisciplinary health providers to identify new strategies to avoid drug interactions, particularly for the patients with polypharmacy status.