A 44-year-old HIV-infected male, having a low CD4 count, was on antiretroviral therapy for the last 2 months, when he developed a skin rash. He gave a history of solitary unprotected extramarital sexual contact 6 months before onset of the rash. Dermatological examination revealed a bilaterally symmetrical, maculopapular erythematous rash involving the palms, forearms, and neck. He showed a positive sign of Buschke-Ollendorff. In the meanwhile, the CD4 count had improved to 196 cells/mm³ from the previous count of 92 cells/mm³ and the viral load had decreased. Serum venereal disease research laboratory (VDRL) test was reactor at 1:64. He was found to be positive result for treponema pallidum hemagglutination test. Skin biopsy revealed features of secondary syphilis. The rash responded well to a single injection of benzathine penicillin, resulting in the lowering of the VDRL titers. There was no evidence of neurosyphilis. This is a very rare instance of secondary syphilis manifesting as immune reconstitution syndrome in an HIV-positive patient.