Abstract Objective This study aimed to assess weight gain associated with treatment switching to INSTI-based regimens in people living with HIV (PLWH) and to determine whether it is accompanied by worsening features of hypertension, dyslipidemia, or hyperglycemia. Methods In this two-center retrospective observational study, we assessed weight gain and metabolic features in PLWH who switched to an INSTI-based regimen (study group) as compared to patients who remained on a non-INSTI regimen (control group) over a 24-month follow-up period. Results One-hundred seventy-four PLWH were included in the study group, and 175 were included in the control group. The study group gained 2.51 kg ± 0.31 (mean ± standard deviation) over the 2 years of follow-up, while the control group gained 1.1 ± 0.31 kg over the same time course (p