Classic studies as well as current clinical trials of psilocybin and LSD demonstrate that these substances alter cognitive and affective processes related to the theme of death, leading to reductions in death anxiety, increases in its acceptance, and beliefs in its transcendence. However, the psychological mechanisms underlying these changes remain unknown. Additionally, to date, no studies have systematically investigated death processing in ayahuasca users. The present cross-sectional study addresses these issues by investigating death-related processes, as well as their potential mediators, in ayahuasca veterans (N=54) compared to matched controls (N=53). For this purpose, an exhaustive battery of questionnaires and behavioral measures was employed, targeting fear and anxiety of death, its acceptance, avoidant related behaviors, emotional load, and the accessibility of death related thoughts. Tested mediators included personality, ontological beliefs, and impermanence awareness. As expected, results indicated more relaxed death processing for the ayahuasca group on all measures, except for death thought accessibility where no differences were found. Importantly, the mediation analyses showed that while personality indices and ontological beliefs did not mediate group differences on any of the death processing measures, impermanence acceptance mediated group differences on all of them. Finally, within the ayahuasca group, ego dissolution depth, but not lifetime intake habits, predicted degree of impermanence acceptance. These findings demonstrate for the first time robust and extensive cross-sectional differences in how death is processed between psychedelic and non-psychedelic users. Even more importantly, they highlight the previously ignored role of impermanence acceptance as a uniquely effective psychological mechanism of change.