OBJECTIVE: Although ayahuasca-a plant-based psychedelic-is discussed as promising in the treatment of posttraumatic stress disorder (PTSD), evidence so far remains limited to retrospective case reports and qualitative surveys. No study to date has examined whether ayahuasca results in prospective and clinically meaningful changes in trauma symptoms across individuals with PTSD symptoms. METHOD: To address this gap, we conducted a convergent mixed-methods case series study on eight military veterans with PTSD who participated in a 3-day ayahuasca intervention in Central America. Clinically meaningful changes from pre- to posttreatment and at a 3-month follow-up were assessed in three ways using: (a) PTSD checklist-5 (PCL-5); (b) experience sampling measurement of momentary PTSD and mood symptoms; and (c) an open-ended survey on perceived benefits. RESULTS: The majority (87.5%; 7/8) of participants demonstrated reliable and/or clinically significant changes in PCL-5 symptoms by posttreatment, which were maintained by 70% (5/7) of veterans by the 3-month follow-up. On average, veterans also reported significant improvements in momentary PTSD symptoms, as well as negative and positive affect in daily life posttreatment, with 63% (5/8) reporting moderate-to-large improvements in these domains. Broad themes characterizing the perceived benefits of ayahuasca included deep positive emotions, decentering/acceptance, and purpose in life; adverse acute experiences were, however, reported. CONCLUSIONS: This study provides preliminary support for the clinically meaningful and lasting benefits of a brief ayahuasca intervention on PTSD/mood symptoms in military veterans.