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Background People with human immunodeficiency virus (HIV) smoke at much higher rates than the general population, resulting in higher risk for tobacco-related morbidity and mortality. The efficacy of smoking cessation interventions among people with HIV in lower-middle-income countries remains unclear. Methods We conducted a randomized, 2 × 2 factorial design trial based in Nairobi, Kenya, to evaluate the efficacy of bupropion versus placebo, and a culturally tailored behavioral cessation therapy, called Positively Smoke Free (PSF), versus standard of care for people with HIV who smoke. The primary outcome was 7-day point prevalence abstinence confirmed by exhaled carbon monoxide <7 ppm at 36 weeks. Results Between June 2020 and August 2023, 300 participants were randomly assigned. Most participants were men (71.4%) who were moderately dependent on nicotine (Fagerström Test of Cigarette Dependence, mean [SD]: 4.5 [2.3]; range: 0-10; higher scores represent greater physical dependence on nicotine); nearly all participants (99.7%) were taking antiretroviral medication. At 36 weeks, 31.3% of participants who received bupropion were abstinent from smoking, compared with 13.3% in the placebo group (odds ratio, 2.95; 95% confidence interval [CI], 1.64-5.32, P<0.001). Among participants randomized to receive PSF therapy, 29.5% were abstinent from smoking, compared with 14.9% in the standard of care group (odds ratio, 2.39; 95% CI, 1.34-4.25, P=0.003). The combination of bupropion+PSF was associated with increased abstinence compared with either bupropion (38.9% vs. 23.6%; odds ratio, 2.06; 95% CI, 1.00-4.23) or PSF (38.9% vs. 20.3%; odds ratio, 2.50; 95% CI, 1.20-5.24) alone. Participants randomized to receive bupropion were significantly more likely to report excessive sweating compared with placebo (50.7% vs. 37.6%; P=0.024). Conclusions Both bupropion and PSF cessation counseling were effective in promoting abstinence from smoking at 36 weeks. The combined intervention was associated with higher abstinence rates than either therapy alone. [ABSTRACT FROM AUTHOR]