Background: The most common serious adverse effects (AEs) associated with NSAID therapy are bleeding and perforated gastroduodenal ulcers. These AEs are dose related, and reduced oral clearance of NSAIDs associated with polymorphisms of cytochrome P450 (CYP) would, theoretically, increase the risk for AEs. Objective: The purpose of this study was to determine whether polymorphisms of the CYP2C9 genotype are associated with the development of serious complications of NSAID-related ulcers. Methods: We examined the records of patients with complications of serious NSAID-related ulcers who were hospitalized from November 2001 to December 2003. Diagnosis was confirmed by endoscopy or abdominal surgery, and a group of consecutive subjects was identified for genetic analysis. CYP2C9 allele frequencies were determined and compared with those in a matched cohort of subjects receiving stable weekly maintenance doses of oral coumarin anticoagulants. Allele frequencies also were compared with those in matched cohorts from earlier studies. Results: All 26 subjects with serious NSAID-related ulcers were white, 15 (58%) were female, and the median age was 74.5 years (range, 32-96 years). All 87 subjects in the reference group were white, 24 (28%) were female, and the median age was 69 years (range, 48-81 years). CYP2C9 genotype frequencies did not differ significantly between subjects with serious complications of NSAID-related ulcers and subjects using oral coumarin anticoagulants. The genotype frequencies in both groups were similar to those reported in previous studies in white subjects. Conclusion: The CYP2C9 genotype was not a significant or clinically relevant risk factor in the development of serious NSAID-related ulcers in this group of subjects. (Clin Ther. 2006;28:1670-1676) Copyright (c) 2006 Excerpta Medica, Inc.