Pythium insidiosum is an oomycete pathogen known to rarely cause invasive infections in humans. Childhood infections are even more unusual, particularly in North America. We recently cared for a 14-year-old girl with fatal disseminated pythiosis who apparently acquired her infection in Texas. Our patient had Diamond-Blackfan anemia, requiring monthly red cell transfusions since infancy with resultant iron overload. She presented with pelvic pain, which progressed to osteomyelitis of multiple pelvic bones followed by vascular invasion and occlusion of bilateral iliac and femoral arteries refractory to anticoagulation, localized tissue plasminogen activator therapy, and surgical embolectomy. Despite administration of a broad range of antibiotic and antifungal therapy, as well as directed immunotherapy, the patient died with disseminated pythiosis. Pythiosis is an unfamiliar pathogen in the United States and extremely difficult to treat, necessitating early diagnosis and urgent medical and surgical intervention when practical for improved prognosis.