Restoration of specific immune responses by combined antiretroviral therapy (cART) in patients infected with human immunodeficiency virus (HIV) may paradoxically cause an inflammatory reaction known as immune reconstitution inflammatory syndrome (IRIS). We report the emergence of giant nodules of molluscum contagiosum (MC) on the face and thighs 2 months after initiation of cART in a 45-year-old male patient with acquired immune deficiency syndrome. To the best of our knowledge, our report describes the first case of MC probably unmasked during IRIS from India.