Abstract R. M. Werner and J. A. Vick. Resistance of the opossum ( Didelphis virginiana) to envenomation by snakes of the family Crotalidae. Toxicon 15, 29–33, 1977.—Whether the North American opossum, Didelphis virginiana, has a natural resistance to envenomation by 12 species of snakes from the families Crotalidae, Viperidae, Elapidae, and Hydrophidae was studied. Challenge of the anesthetized opossum was by actual snakebite, and by i.m. or i.v. injection of 4–60 times the dose known to be lethal to susceptible mammals. Some animals that survived the snakebite were also given venom intravenously 40–90 min after bite challenge. Heart and respiratory rate, EKG, and blood pressure were monitored for 2 hr after envenomation, and surviving animals were observed for signs of poisoning for 30 days. The opossum survived the venom of the following snakes of the Family Crotalidae: eastern diamondback rattlesnake, western diamondback rattlesnake, copperhead, cottonmouth moccasin, Korean mamushi, and Central American moccasin. It died when challenged with the venom of the Indian cobra, Chinese cobra, coral snake, cape cobra, puff adder, and sea snake. These findings show promise of the opossum being an excellent experimental animal for venom research, particularly by identifying its protective mechanisms.