Introduction: Tenofovir is integral to antiretroviral therapy (ART) and pre‑exposure prophylaxis (PrEP) for HIV; however, neuropsychiatric adverse events (NPAEs) associated with its use have not been systematically investigated., Objectives: This systematic review aimed to characterize common NPAEs occurring during tenofovir‑based ART and PrEP, and to assess the specific role of tenofovir in their emergence., Patients and Methods: Four literature databases and 3 trial registries were searched up to December 31, 2023 for randomized controlled trials reporting NPAEs in treatment‑naive adults receiving tenofovir‑based ART or PrEP. Meta‑analyses were conducted to compare tenofovir (with / without emtricitabine) with placebo and tenofovir alafenamide-based with tenofovir disoproxil fumarate-based regimens., Results: A total of 69 trials (62 on ART, 7 on PrEP) including 29 340 patients on tenofovir‑based therapies identified headache, dizziness, insomnia, and depression as common NPAEs, especially in HIV studies. Meta‑analyses of tenofovir (with / without emtricitabine) vs placebo only indicated an increased risk of dizziness (odds ratio [OR], 1.32; 95% CI, 1.09-1.59; P = 0.004). Comparisons between tenofovir alafenamide and disoproxil fumarate did not show significant differences in NPAE risks, although sensitivity analyses suggested a higher risk of headache with tenofovir alafenamide in HIV studies (OR, 1.24; 95% CI, 1.01-1.52; P = 0.04)., Conclusions: Common occurrence of NPAEs in tenofovir‑based HIV multidrug regimens highlights the need to screen HIV patients for neuropsychiatric complications. The lack of effect of tenofovir, as compared with placebo, for most analyzable NPAEs suggests its favorable safety profile. However, a possible increase in the dizziness risk on tenofovir, and a potentially elevated risk of headache on tenofovir alafenamide- as compared with tenofovir disoproxil fumarate-based regimens in HIV therapy merit further investigation.