Pyometra is a serious, life-threatening disease of both domestic and non-domestic species often requiring ovariohysterectomy to preserve the life of the animal. Medical management of pyometra has been successful in domestic and non-domestic species, and the consideration of such treatment is of marked importance in a critically endangered species. Of the canids, the red wolf (Canis rufus) is second only to African hunting dogs (Lycaon pictus) in terms of the prevalence of both cystic endometrial hyperplasia and pyometra. In this report, three red wolves were medically managed for pyometra. Aside from vaginal discharge, none of the wolves exhibited clinical signs, nor were there reflective inflammatory changes in the laboratory findings. All wolves received standard treatment for pyometra, including prostaglandin F₂α and antibiotic therapy, while one wolf was more aggressively managed with uterine lavage. Pyometra recurred in two of the treated wolves, while the most aggressively managed wolf continues to show ultrasonographic resolution 2 yr posttreatment. Aggressive medical management of pyometra should be considered a treatment option in certain red wolf females, as it may preserve the animal's reproductive potential.