Quitting smoking among people living with HIV/AIDS (PLWHA) is a priority. However, PLWHA and clinicians working with PLWHA are reluctant to use tobacco use treatments out of concern that smoking cessation can diminish anti-retroviral therapy (ART) adherence and quality of life (QoL) and increase psychiatric symptoms. This secondary analysis from a placebo-controlled varenicline trial for tobacco dependence among PLWHA ( = 179) examined if smoking cessation at the end of treatment (EOT) was associated with changes in ART adherence, QoL, anxiety and depression symptoms, and varenicline side effects. ART adherence was not affected by smoking cessation ( > 0.05), remaining ≥98% for all participants. Across 8 QoL subscales, 7 remained unchanged over time across smokers and abstainers; side effects were not associated with cessation. Controlling for baseline smoking rate, adherence to varenicline/placebo and counseling, and treatment arm, participants who had quit smoking at EOT reported a significant reduction in depression ( = -1.657, 95% CI: -2.893, -0.422, = .009) and anxiety ( = -1.434, 95% CI: -2.812, -0.56, = .041) and increased life satisfaction ( = 0.88, 95% CI: 0.21, 3.275, = .027). When PLWHA quit smoking they may not experience adverse clinical outcomes including ART non-adherence and may experience beneficial psychological effects, supporting the use of FDA-approved smoking cessation treatments among PLWHA.