This study assessed the "real-world" risk of serious gastrointestinal (GI) toxicities, defined as perforations, ulcers and bleeds (PUBs) in a U.S. representative population that was using two commonly available over-the-counter (OTC) non-selective nonsteroidal antiinflammatory drugs (NSAIDs), naproxen or ibuprofen with or without concomitant aspirin usage. A retrospective review of a commercially available electronic medical record (EMR) database containing the ambulatory health record data for over 3.2 million individuals was conducted. Subjects were eligible for inclusion in the study if they received an OTC dosage of naproxen (220 mg) or ibuprofen (200 mg). An index date for each subject was defined as the first mention of an OTC NSAID in the medication list of the EMR dataset. Subjects were excluded from the analysis if they met any criteria, which can lead to GI bleeding complications. The dataset was analyzed for PUBs, as indicated by the ICD-9 diagnosis codes for gastric, duodenal, peptic, or gastrojejunal ulcers, or GI hemorrhage, as well as the concomitant use of aspirin. A pre/post-analysis was conducted using a case-crossover design with subjects as their own controls. The index date was the defining event, in order to determine the odds ratio associated with OTC NSAID usage. A pre-index time period of 365 days was used for prior PUBs. For the post-index time period, only PUBs that occurred within 90 days of the OTC NSAID index date were considered. The data set contained 11,957 subjects on naproxen and 38,507 subjects on ibuprofen. In both cases, OTC NSAID usage was associated with a statistically significant increase in the odds ratio for PUBs. Subjects on ibuprofen had an odds ratio of 1.38 (95% CI 1.07-1.78, P=0.01). Naproxen subjects exhibited an odds of 1.54 (95% CI 1.04-2.28, P=0.03). The concomitant aspirin population consisted of 2,328 naproxen subjects and 4,843 ibuprofen subjects. Concomitant aspirin usage was also associated with a significantly higher risk for PUBs than the corresponding monotherapy. Subjects taking both ibuprofen and aspirin had an odds ratio of 3.36 (2.36-4.80, P<.00001), while those on naproxen and aspirin had an odds ratio of 2.07 (1.23-3.49, P=.005) relative to those subjects on ibuprofen and naproxen monotherapy, respectively. Utilizing a national electronic medical record database representing patients seen predominantly in a primary care setting, this study has documented the "real-world" risk associated with the use of two common OTC NSAIDs, as well as the increased risk associated with concomitant aspirin use in this population.