Behavioral and psychiatric problems are common in patients with Prader-Willi syndrome (PWS), while physical complaints such as pain, fever, and vomiting are rare due to a high pain threshold and dysregulation of temperature control. PWS patients have an increased mortality rate, some due to undiagnosed life-threatening diseases. We describe 2 patients with PWS whose behavioral changes, initially thought to be part of their behavioral phenotype, delayed the final diagnosis of a life-threatening underlying illness. A 13-year-old girl with PWS presented with a sudden change in behavior including aggression, scratching, and self-injury. She was seen by several health care providers, and after 5 months the diagnosis of pyosalpinx was made, for which laparoscopic resection of an infected tailgut cyst was performed, resolving the behavioral symptoms. A 38-year-old man with PWS presented with recurrent vague inguinal pain and nonepileptic seizures. After several years of consulting physicians and psychiatrists, including several hospital admissions, the diagnosis of bilateral inguinal hernia was made. After surgical correction, the pain and seizures ceased. In PWS patients presenting with unexplained behavioral changes and unusual somatic complaints, clinicians should perform an extensive clinical examination and consider underlying physical illness rather than attribute the problem to the behavioral phenotype.