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A 42-year-old woman presented to the emergency department with progressive painful discoloration of the digits of her right foot and symptoms previously diagnosed as neuroma. She was admitted to the hospital for dorsalis pedis arterial occlusion and ischemic foot pain. Despite attempts to restore perfusion to the right leg, ischemia of the right foot persisted and progressed to digital gangrene. The patient subsequently required right transmetatarsal amputation and eventually below-the-knee amputation. After extensive inpatient vascular and hematologic work-up of this otherwise healthy woman, test results revealed that she had protein S deficiency, hepatitis C, and human immunodeficiency virus type 1. In addition to describing this patient’s evaluation and treatment, we review protein S deficiency, including its correlation with human immunodeficiency virus type 1 infection and laboratory diagnosis. This case promotes awareness of protein S deficiency and serves as a reminder to the physician treating patients with vascular compromise and a history of human immunodeficiency virus type 1 to include protein S deficiency in the differential diagnosis. (J Am Podiatr Med Assoc 97(2): 151–155, 2007)