Platelet-endothelial cell adhesion molecule 1 (PECAM-1/CD31) has been identified as an endothelial cell receptor of Plasmodium falciparum-infected erythrocytes. The significance of adhesion of infected erythrocytes to this receptor in malaria infection has not been determined. We have therefore studied the association of the functional mutation CTG-->GTG (Leu-->Val) in codon 125 of the Cd31 gene with severe disease in 2 case-control studies of malaria in Madang Hospital, Papua New Guinea, and in Kilifi District Hospital, Kenya. We analyzed data from 442 cases and controls from Papua New Guinea and data from 396 cases and controls from Kenya. The codon 125 polymorphism was not associated with severe malaria in either study. We conclude that the presence of CTG-->GTG (Leu-->Val) substitution in codon 125 in CD31 is not associated with protection from severe malaria, and we suggest that selective forces other than malaria may maintain this high-frequency polymorphism.