Latrodectus mactans antivenin is a safe and effective therapy for severe black widow spider envenomations when given to most patients. We report a case of a 37-year-old male with a history of asthma that was given L. mactans antivenin for symptoms related to a black widow envenomation and developed a severe anaphylactic reaction resulting in cardiac arrest. When traditional therapies failed, the patient was given methylene blue for anaphylactic shock resulting in a 30-h period of hemodynamic stability. Despite initial resuscitation, the patient ultimately died 40 h after presentation. Under the right circumstances, L. mactans antivenin remains a safe and effective therapy for severe black widow envenomations. However, anaphylaxis is a risk for those receiving this therapy, even when the antivenin is diluted and given as an infusion. We report the first death related to diluted L. mactans antivenin given as an infusion.