Skin manifestations of immune reconstitution inflammatory syndrome in response to highly active antiretroviral therapy may account for up to 50% of the clinical presentations in this syndrome. Viable or dying infective antigens, host antigens, tumoral antigens, and others may target immune reconstitution inflammatory syndrome, resulting in a wide spectrum of clinical manifestations. We describe a 26-year-old HIV-infected man who had started highly active antiretroviral therapy a few months earlier. He developed multiple linear nodules following the superficial veins in both legs. Histopathologic examination demonstrated a mostly septal panniculitis with features of superficial thrombophlebitis. We propose that superficial thrombophlebitis should be added to the list of clinical manifestations of this newly observed immune restoration disease.