Significant envenomation from a rattlesnake bite can result in tremendous local tissue destruction, and severe envenomation can cause death. To avoid these outcomes, we recommend the aggressive infusion of antivenin (Crotalidae) polyvalent; 15 to 20 vials are required on average. Management considerations discussed in this article include hypersensitivity to horse serum, hematologic abnormalities, symptoms of envenomation, care of the bite site, and care of patients with severe symptoms.