Thrombophilia may cause thrombotic venous occlusion in the femoral head, with venous hypertension and hypoxic bone death, leading to Legg-Perthes disease. Resistance to activated protein C, the most common thrombophilic trait, was measured in 64 children with Legg-Perthes disease. Genomic deoxyribonucleic acid was studied to delineate the CGA-->CAA substitution at position 1691 of the Factor V Leiden gene responsible for resistance to activated protein C. The activated protein C ratio was calculated by dividing clotting time obtained with activated protein C-calcium chloride by clotting time obtained with calcium chloride alone. Resistance to activated protein C, with a low activated protein C ratio (less than 2.19, the 5th percentile for 160 normal pediatric controls) was the most common coagulation defect, found in 23 of 64 children with Legg-Perthes disease versus 7 of 160 pediatric controls. Eight of 64 children with Legg-Perthes disease had a low activated protein C ratio and the mutant Factor V gene (7 heterozygotes, 1 homozygote) versus 1 of 101 normal pediatric controls. Two or 3 generation vertical and horizontal transmission of heterozygosity for the mutant Factor V gene was found in 4 of the 8 kindreds. Of 64 children with Legg-Perthes disease, only 14 (22%) had entirely normal coagulation measures. Resistance to activated protein C appears to be a pathogenetic cause of Legg-Perthes disease.