OBJECTIVES: Nonsteroidal anti-inflammatory drugs (NSAIDs) can cause peptic ulcer disease and upper GI bleeding. Acid suppression medications effectively treat NSAID-induced ulcers. However, it is unknown what effect the availability of proton pump inhibitors and over-the-counter preparations of NSAIDs and histamine type 2 receptor antagonists have had on population rates of hospitalization and mortality from GI toxicity. This study examines trends in hospitalization and mortality rates from GI toxicity during the 1990s. METHODS: We performed an analysis of secular trends of hospitalization and mortality rates from peptic ulcer disease, upper GI bleeding, and any GI bleeding using data from the National Hospital Discharge Survey, comparing them with sales of NSAIDs, aspirin, and acid suppression medications from 1992 to 1999. RESULTS: From 1992 to 1999, annual rates of hospitalization and mortality per 100,000 population for peptic ulcer disease declined from 205 to 165 and 7.7 to 6.0, respectively; calendar year was negatively correlated with both peptic ulcer disease hospitalization rates (ρ = −0.88, p = 0.007) and mortality rates (ρ = −0.71, p = 0.058). In contrast, these correlations did not reach statistical significance for upper or any GI bleeding ( p > 0.1 for all comparisons). Sales of acid suppression medications were negatively correlated with peptic ulcer disease hospitalization rates (ρ = −0.76, p = 0.037) and mortality rates (ρ = −0.83, p = 0.015). Sales of NSAIDs were not positively correlated with hospitalization or mortality rates from peptic ulcer disease or GI bleeding ( p > 0.2 for all comparisons). CONCLUSIONS: Despite changing patterns of use of NSAIDs and acid suppression medications during the 1990s, mortality rates from GI bleeding and peptic ulcer disease have been relatively stable, with an apparent decline in hospitalization rates and mortality from peptic ulcer disease. Changing rates of peptic ulcer disease morbidity and mortality were temporally related to increasing sales of antiulcerants but not to change in sales of NSAIDs.