Background: Ayahuasca’s effects on symptoms of depression have generated considerable optimism. Clients frequently report more concern about some symptoms than others, and available treatments alter symptoms differentially. Few studies address the symptom specificity of this psychoactive brew. Aims: We examined self-reported effects of ayahuasca on the individual symptoms of depression assessed by the 10-item short-form of Center for Epidemiological Studies of Depression (CESD-10). Methods: We asked over 120 participants to complete a retrospective assessment of CESD-10 symptoms one month before and one month after using ayahuasca. Results: Participants indicated that ayahuasca had a larger influence on affective symptoms like hope, depressed mood, and happiness, than cognitive, interpersonal, and somatic symptoms like restless sleep, loneliness, and difficulty focusing. Conclusions: Potential clients might appreciate identifying if different treatments provide more relief for some depressive symptoms than others. We examined retrospective reports of ayahuasca’s potential for differential impact. Those eager to alter hope, happiness, and other affective symptoms will likely find ayahuasca more helpful than those who want an intervention for restless sleep, loneliness, or trouble focusing. This symptom specificity parallels the effects of serotonergic antidepressant medications, suggesting that psychedelic-assisted psychotherapy using ayahuasca might have considerable appeal for those who seek comparable relief but would rather not use prescription serotonergic medications. Jumpstarting psychotherapy with the rapid onset of ayahuasca-induced relief also appears to have potential.