A 44-year-old man known to have human immunodeficiency virus (HIV) infection presented to our clinic with erythroderma, generalized lymphadenopathy, and cutaneous nodules and tumors. After a series of investigations, we confirmed that he had Sézary syndrome. In this paper we describe the immune alterations that occur in both Sézary Syndrome and HIV infection and how these changes together resulted in rapid and overwhelming immune dysregulation in our patient.