More than 17 million people in the U.S. live with cancer and up to 25% of them have major depression. Depression leads to lower treatment adherence, reduced quality of life, and higher rates of mortality in cancer. Yet, interventions used to treat depression in patients with cancer have limited success. Prior trials using psilocybin to treat anxiety and depression associated with cancer suggested improvements in psychological distress. However, treatment in a homogenous psychiatric sample has yet to be investigated. Further, psilocybin has not been given in groups, and in a setting conducive to the “whole person” approach to treatment. This trial built upon previous studies and tested the safety, feasibility, and efficacy of psilocybin therapy in cancer patients diagnosed with major depressive disorder (MDD), with the novel use of group treatment in a cancer center setting. https://clinicaltrials.gov/ct2/show/NCT04593563