The use of aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) may decrease the risk of esophageal adenocarcinoma; however, it is unknown where these agents may act in the proposed pathway from normal mucosa to Barrett’s esophagus to esophageal adenocarcinoma. The aim of the study was to evaluate the association between aspirin and NSAID use and Barrett’s esophagus in a case-control study within a large community-based population. We conducted a case-control study of aspirin/NSAID use and Barrett’s esophagus within the Kaiser Permanente Northern California population. Cases had a new diagnosis of Barrett’s esophagus between October 2002 and September 2005; controls were members without a diagnosis of Barrett’s esophagus. Persons with Barrett’s esophagus were less likely to use aspirin than population controls [odds ratio (OR) 0.59, 95 % confidence interval (CI) 0.39-0.87]; a stronger association was found among cases and controls with reflux symptoms (OR 0.49, 95 % CI 0.32-0.75; p value interaction = 0.004). Similar associations were found with the use of either aspirin and/or non-aspirin NSAIDs (OR 0.53, 95 % CI 0.35-0.81), although NSAID use alone was not significantly associated with Barrett’s esophagus (OR 0.74, 95 % CI 0.47-1.16). The strength of the association was highest among persons with at least moderate-to-high total medication intake. Regular use of aspirin or NSAIDs was associated with a decreased risk of Barrett’s esophagus, particularly among persons with gastroesophageal reflux disease symptoms. These findings have implications for chemoprevention, as some of the previously described protective association between aspirin/NSAIDs and esophageal adenocarcinoma may be explained by events that occur prior to the development of Barrett’s esophagus.