Exposure to some antiretroviral drugs, especially integrase strand transfer inhibitors (INsTI)-based combination antiretroviral therapy (cART) has been associated with weight gain in people living with HIV (PLWH) exceeding what would be a "return to health" phenomenon. Notwithstanding the fact that weight gain and obesity are multifactorial, the common epidemiological link in PLWH is INsTI-based cART. Here, we postulate that interference with the melanocortin system (MCS) functioning by INsTI plays an essential role in excess weight gain and obesity in PLWH, similar to disturbances caused by melanocortin receptor (MCR) mutations in the general population and by antipsychotic therapy in psychiatric patients.