Patients who take nonsteroidal anti-inflammatory drugs (NSAIDs) are at increased risk of upper gastrointestinal tract bleeding, which may be prevented with prophylactic prescription of misoprostol. Using data from the literature, we estimated rates of gastrointestinal tract bleeding in NSAID users, direct medical costs, years of life lost, and cost-effectiveness of a 1-year course of misoprostol in three clinical populations of NSAID users: all users, users aged 60 years or older, and users with rheumatoid arthritis. The incremental cost-effectiveness ratios for misoprostol as primary prevention were $667 400 per year of life saved for all NSAID users; $186 700 per year of life saved for users aged 60 years or older; and $95 600 per year of life saved for users with rheumatoid arthritis. Misoprostol as secondary prevention for those who continued to take NSAIDs despite having had an episode of gastrointestinal tract bleeding in the previous year was associated with incremental cost-effectiveness ratios less than $40 000 per year of life saved in all patient groups. We conclude that misoprostol is costly as primary prevention for NSAID-induced gastrointestinal tract bleeding in the groups examined but may be cost-effective as secondary prevention in patients with a proved history of gastrointestinal tract bleeding.