Rationale : Smoking-related disease is a major problem globally. Effective smoking cessation treatments are however limited. Increasing evidence suggests that psychedelics have potential as treatments for substance use disorders and may therefore prove an option in aiding smoking cessation.Objectives : To establish which factors predict smoking cessation in people who reported quitting or reducing smoking following ayahuasca consumption.Methods : A retrospective cross-sectional mixed-method study (quantitative and qualitative design) was undertaken using data from an online survey evaluating peoples’ experiences before and after drinking ayahuasca. Multivariate logistic regression was performed with smoking condition (cessation or reduction/relapse) as a dependent variable and demographics, smoking, ayahuasca-related variables and the mystical experience (MEQ30) as predicting factors.Results : A total of 441 responses were grouped according to self-reported smoking status: cessation (n = 305) or reduction/relapse (n = 136) smoking. Logistic regression showed that mystical experience (OR: 1.03; 95% CI [1.00–1.05]) and frequency of ayahuasca intake (OR: 2.16[1.00–4.70]) were protective factors, while positive mood (measured by the MEQ30) during the ayahuasca experience was a risk factor (OR: 0.91[0.85–0.97]). Qualitative thematic analysis identified eight themes (e.g. acquired awareness, spiritual experience, increased motivation) related to the ayahuasca experience and the process of smoking cessation/reduction.Conclusions : Our results suggest that ayahuasca could be used as a potential tool for smoking cessation, and that effects may be mediated by mystical experience. Given the current burden of smoking-related disease and the limited treatment options, studies are needed to investigate the efficacy of psychedelics in smoking cessation.