Coprescription of gastroprotective agents is a common practice for patients requiring nonsteroidal anti-inflammatory drug (NSAID) therapy, although there is limited evidence that some of these agents are effective. The prostaglandin analog misoprostol and the proton pump inhibitor omeprazole appear to be efficacious in decreasing NSAID-associated ulcers. Misoprostol has also been shown to decrease NSAID-associated gastrointestinal (GI) complications by 40% compared with placebo. Despite the efficacy of these drugs, their effectiveness in the general population has not yet been adequately determined with respect to reduction of symptoms and improvement in patient quality of life. Sucralfate and bismuth appear to be largely ineffective, and histamine receptor antagonists, when given at traditional ulcer-healing doses, decrease symptoms and duodenal ulcers only. The issue of outcomes research, therefore, needs to be more fully incorporated into any analysis of the effectiveness or cost-effectiveness of the widespread clinical use of such gastroprotective drugs.