OBJECTIVE: This study evaluated body mass index (BMI) and weight changes in people living with human immunodeficiency virus (HIV-1; PLWH) initiated on single-tablet darunavir/cobicistat/emtricitabine/tenofovir alafenamide (DRV/c/FTC/TAF) or bictegravir/FTC/TAF (BIC/FTC/TAF). METHODS: Electronic medical record (EMR) data for treatment-naïve or virologically suppressed adults with HIV-1 who initiated treatment with DRV/c/FTC/TAF or BIC/FTC/TAF (index date) were obtained from Decision Resources Group's EMRs (17 July 2017-1 March 2020). Inverse probability of treatment weighting was used to account for differences in baseline characteristics between the two cohorts. BMI and weight changes from pre-index to 3, 6, 9 and 12 months following the index date were compared using weighted mean differences (MDs). The time until an increase in BMI or weight ≥5% or ≥10% was compared using weighted hazard ratios (HRs). RESULTS: The weighted DRV/c/FTC/TAF and BIC/FTC/TAF cohorts comprised 1116 and 1134 PLWH, respectively (mean age = ∼49 years, females: ∼28%). Larger increases in BMI and weight from pre-index to each post-index time point were observed in PLWH initiating BIC/FTC/TAF vs DRV/c/FTC/TAF (12 months: MD in BMI = 1.23 kg/m,  < .001; MD in weight = 2.84 kg [6.26 lbs],  = .008). PLWH receiving BIC/FTC/TAF were significantly more likely to experience weight gain ≥5% (HR = 1.76,  = .004) and ≥10% (HR = 2.01,  = .020), and BMI increase ≥5% (HR = 1.77,  = .004) and ≥10% (HR = 1.76,  = .044) than those receiving DRV/c/FTC/TAF. CONCLUSIONS: BIC/FTC/TAF was associated with greater BMI and weight increases compared to DRV/c/FTC/TAF. Weight gain and its sequelae may add to the clinical burden of PLWH and should be considered among other factors when selecting antiretroviral single-tablet regimens.