Background and aims: 5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a potent, short-acting psychedelic that produces strong hallucinogenic effects. The association between the context (i.e., set and setting) of 5-MeO-DMT use and the acute and enduring effects of the substance is unknown. Therefore, this study examined these associations using secondary data from two cross-sectional survey studies. Methods: The acute and enduring effects of inhaled synthetic 5-MeO-DMT were compared between individuals who used 5-MeO-DMT in a non-structured context (NSC; n = 216, female = 10%, Mage = 35.5, SD = 11.8) and those who used in a structured context (SC; n = 362, female = 45%, Mage = 47.7, SD = 13.3). Questionnaires were administered online and responses were anonymized for privacy purposes. Respondents were asked to retrospectively rate their first experience with synthesized 5-MeO-DMT on measures of mystical experience, challenging experience, and enduring effects. Results: Both groups endorsed high ratings on the Mystical Experience Questionnaire; however, mean scores were significantly higher in the SC group compared to the NSC group. Similarly, the proportion of respondents who had a complete mystical experience was significantly larger in the SC group (83%) compared to the NSC group (54%). Ratings of enduring effects (i.e., meaningfulness, spirituality, and well-being) were also significantly higher, and the intensity of challenging experiences was significantly lower, in the SC group compared to the NSC group. Conclusions: 5-MeO-DMT appears to occasion mystical-type experiences with enduring positive effects, which are more intense when 5-MeO-DMT is administered in a safe and supportive context. Future prospective experimental studies should examine the effects of 5-MeO-DMT and its interactive relationship with supportive contextual factors. Keywords: 5-MeO-DMT, psychedelics, context, set and setting, mystical experience, challenging experience