Molluscum contagiosum is a viral infection caused by the Poxvirus characterized by multiple umbilicated papules. It is common in children and can be present at any body site. Severe molluscum is common in immunocompromised patients. We report a 20-year-old HIV-positive individual with widespread molluscum contagiosum, recalcitrant to topical therapy, under antiretroviral therapy, who was treated with oral isotretinoin and had a dramatic outcome. Although studies are needed to confirm the effectiveness of oral isotretinoin therapy in molluscum contagiosum, its easy availability, cost, and excellent safety profile appear to offer a promising therapeutic option.