The purpose of this study was to compare the efficacy and safety results for AMBER and EMERALD patients with and without baseline neurological and/or psychiatric comorbidities (NPCs). Both the AMBER and EMERALD studies, which randomized participants to receive 800 mg darunavir, 150 mg cobicistat, 200 mg emtricitabine, and 10 mg tenofovir alafenamide, respectively, were conducted on treatment-naive populations. The primary purpose of this post hoc study was to compare individuals with and without baseline NPCs in terms of virological response (HIV-1 RNA 50 copies/mL) at week 48, using an intent-to-treat US Food and Drug Administration snapshot analysis. Baseline NPCs were found in 24% (88/362) of the D/C/F/TAF arm and 27% (99/363) of the control arm in the AMBER study, whereas 39% (294/763) of the D/C/F/TAF arm and 44% (163/378) of the control group were found to have NPCs in the EMERALD study. Depression was the most common psychiatric NPC and headache the most common neurological NPC in both studies’ baseline periods. D/C/F/TAF led to high virological response rates at weeks 48 (range 86%-95%) and 96 (range 80%-91%), regardless of baseline NPCs. There were no premature withdrawals due to a neurological or mental adverse event in either study among subjects with a baseline NPC. Some people with HIV-1 and NPCs may benefit from D/C/F/TAF.