Association of a mutation in the coagulation factor V gene (FV Leiden) with deep vein thrombosis and pulmonary thromboembolism has been well documented in the literature, but no study has specifically screened cases of fatal pulmonary thromboembolism for the mutation. This study sought to determine whether FV Leiden plays a role in the pathogenesis of fatal pulmonary thromboembolism. We isolated DNA from archived paraffin-embedded tissues derived from 46 necropsy cases in which pulmonary thromboembolism was listed as the cause of death (n = 27) or was secondarily associated with death (n = 19). FV Leiden genotypes were determined by using polymerase chain reaction and MnlI digestion of amplified products. The Leiden mutation occurred in the heterozygous state in one (2.1%) of the necropsy specimens. The prevalence of the mutation was higher (8.7%) in gender- and ethnic-matched blood donor controls. The FV Leiden mutation is not independently associated with fatal pulmonary thromboembolism in the group of patients analyzed. The results suggest different etiologies for nonfatal, chronic deep vein thrombosis/pulmonary thromboembolism and fatal, acute pulmonary thromboembolism.