Activated protein C resistance (APCR) may occur in up to one fourth of patients with venous leg ulcers and has recently emerged as the most frequent cause of venous thrombosis. Deep venous thrombosis often precedes deep venous insufficiency and is of major importance in the pathogenesis of venous leg ulcers. APCR is most frequently caused by a point mutation in the factor V gene (fV R506Q), resulting in reduced inactivation of activated factor V and imbalance of the hemostatic system. Recent data suggest that APCR/fV R506Q may be common in patients with venous leg ulcers. We review APCR as a genetically determined risk factor that may contribute to the development of venous leg ulcers. New diagnostic developments are discussed, and therapeutic guidelines specifically directed toward the prevention of thrombosis are suggested. (J Am Acad Dermatol 1997;36:616-20.)