Rationale <p>There is growing enthusiasm around the potential of psychedelics to transform how individuals engage with the theme of death, with self-report evidence suggesting these substances foster acceptance and reduce fear-of-death. Yet, given extensive evidence linking unconscious processes to mortality avoidance, current research efforts remain limited and call for implicit and neurobiology-based measures.</p> Objectives &amp; methods <p>To this end, we applied a validated no-report magnetoencephalogram (MEG) visual MisMatch Response (vMMR) paradigm to assess whether long-term ayahuasca users (<i>N</i> = 50), compared to previously published data from healthy controls and experienced meditators, show self-specific neurophysiological markers of death-denial/acceptance. Self-report and behavioral measures of fear-of-death were also collected.</p> Results <p>Cluster-based permutation analyses on the vMMR data showed that ayahuasca users’ brains responded to the coupling of death and self-stimuli in a manner indicating denial rather than acceptance. At the same time, 1-way ANOVAs and <i>post hoc t</i>-tests analyses indicated that the ayahuasca group evidenced less implicit fear-of-death than the general population, and less explicit fear-of-death than both the general and meditator samples. Further correlation analyses on the neurophysiological ayahuasca sample death-denial marker supported its construct validity by associating it with less self-reported death acceptance and reduced accessibility to death-related thoughts. Finally, death-denial was linked to greater life satisfaction, supporting its adaptive role.</p> Conclusions <p>These findings provide preliminary evidence that while ayahuasca may alter how humans interact with the theme of death on conceptual and affective levels of cognitive processing, on automatic, perceptual unconscious levels of self-specific processing, death-denial processes appear to remain intact.</p>