Molluscum contagiosum (MC) is a common, self-limited cutaneous infection in immunocompetent individuals. However, in immunocompromised individuals the infection often has an atypical presentation and can be difficult to eradicate, making both the diagnosis and treatment challenging. Due to advancements in the management of patients with human immunodeficiency virus (HIV) and cancer, there is a growing population of immunosuppressed individuals, signaling the need for dermatologists to recognize and manage related skin diseases. We present a case of an atypical MC eruption in a patient on biologic therapy for psoriasis and an unrecognized underlying HIV infection, followed by a current review of the presentation and treatment of MC in various immunosuppressed states. With a growing population of immunosuppressed patients, it is important to recognize MC as a potential indicator of underlying immunosuppression. Testing for HIV should be offered to any patient starting immunosuppressive therapy such as biologic agents.