We report a cohort study of fatal upper GI hemorrhage and/or perforation in relation to use of nonsteroidal anti-inflammatory drugs (NSAIDs) among the one million residents of Saskatchewan Canada in 1983. All hospitalized cases of GI hemorrhage and/or perforation with a fatal outcome were identified using the records linkage system of the Saskatchewan Department of Health. Discharge summaries and autopsy records were reviewed to select the cases of upper GI hemorrhage or upper GI perforation and to exclude cases in which known risk factors were present. The 134,060 residents who filled one or more prescriptions for an NSAID in 1983 were identified and individually linked to their hospital records by patient identification number. The age- and gender-specific incidence of fatal upper GI hemorrhage and/or perforation in the absence of risk factors in users was compared to that in nonusers, controlling for recent history of upper GI disease. Fatal upper GI hemorrhage or perforation in temporal association with NSAIDs is extremely rare in persons younger than 75 years of age. No temporally-related cases occurred in male NSAID users age 75 and older, but NSAID usage in this group was limited. Among women age 75 and older, the rate in users was higher than in nonusers, with the highest rate being in female NSAID users age 75 and older with a recent history of upper GI disease. Total mortality among women age 75 and older was slightly lower among users than among nonusers. Physicians who prescribe NSAIDs to patients age 75 and older should be aware of the potential risks, particularly in those with predisposing factors such as a history of upper GI disease.