Background: 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. Methods: Phase II, single-center, open label trial, where 30 patients received a dose of 25 mg of psilocybin. Inclusion criteria: 1) age ≥ 18 years, 2) met criteria for MDD, 3) a Hamilton Depression Rating Scale score ≥ 18 at baseline, 4) diagnosis of a malignant neoplasm. Patients who had curative treatment for cancer as well as those with advanced metastatic disease were included. Patients were divided into cohorts and they received 1 group preparation session, simultaneous administration of psilocybin, and 2 group integration sessions. Therapeutic care was also provided before, during, and after the session using the 1:1 model of psychological support. The primary outcome measures for safety were adverse events, vital signs, ECGs, blood tests, and suicidality scores (C-SSRS). The secondary and exploratory outcome measures consisted of 15 assessments conducted at baseline and post-treatment at day 1, week 1, week 3, and week 8 to determine the efficacy of treatment. Results: A total of 30 patients were enrolled over the course of only 8 months with an attrition rate of 0%. All completed the trial with no serious adverse events. Beyond high tolerability of the treatment, we also found a clinically meaningful change in depressive symptoms. After a single administration of psilocybin therapy, the average score on the Montgomery Asberg Depression Rating Scale (MADRS) dropped by 19.1 points (95% CI, 22.3 to 16.0, p < 0.0001). A sustained response rate (a decrease of ≥ 50% in the MADRS score from baseline to week 8) was seen by 24 patients. 50% of patients showed complete remission of depression symptoms (a MADRS score < 10) one week after treatment, which was sustained for up to 8 weeks. Conclusions: This study adds to the growing body of psilocybin research with promising results showing the safety, feasibility, and efficacy of simultaneous psilocybin treatment in patients with cancer with MDD. The value of group support for patients with cancer was also explored, with implications for increased scalability of psilocybin therapy in real-world settings. Clinical trial information: NCT04593563.