Onychomycosis is frequent in patients with late and advanced HIV disease; immunocompromised patients may develop atypical clinical presentations that can be difficult to control. Current treatment for onychomycosis is based on the prolonged administration of antifungal therapies that may have significant interactions with combined antiretroviral therapy (cART). An improvement in certain HIV-associated opportunistic infections has been associated with initiation of cART. The aim of this study was to analyze the influence of cART on the outcome of onychomycosis in HIV-infected patients. HIV-infected patients with dermatologic lesions attending the National Institute of Respiratory Diseases were asked to undergo physical examination. Detailed clinical histories were recorded. Routine laboratory tests, CD4 T cell count, and HIV viral load were performed. Onychomycosis was diagnosed on the basis of clinical appearance. Nail scrapings were collected from toenails and fingernails. Specimens were analyzed using direct microscopy. Nail changes after cART initiation were assessed by clinical examination. Improvement in onychomycosis was observed in six patients with late and advanced HIV disease after initiation of cART. Complete resolution of onychomycosis was observed in one patient without the use of antifungal therapy; one patient required topical antifungal treatment, and two patients required systemic antifungal treatment to achieve complete resolution. Onychomycosis should be included in the group of pathologies that improve with cART-induced immune reconstitution. The pathogenesis of onychomycosis in HIV disease warrants investigation in the context of cell-mediated immunity restoration.