This open-label feasibility study investigated the safety, feasibility, and efficacy of psilocybin with psychological support in patients with treatment-resistant depression. Twelve patients with moderate-to-severe, unipolar, treatment-resistant depression received two oral doses of psilocybin (10 mg and 25 mg, 7 days apart) in a supportive setting. The primary outcome measure for feasibility was patient-reported intensity of psilocybin's effects, while depressive symptoms were assessed using the 16-item Quick Inventory of Depressive Symptoms (QIDS). Psilocybin was well tolerated by all patients, with no serious or unexpected adverse events. The acute psychedelic effects of psilocybin typically became detectable 30–60 min after dosing, peaked 2–3 h after dosing, and subsided to negligible levels at least 6 h after dosing. The mean self-rated intensity of psilocybin experience was 0.51 (SD 0.36) for the low-dose session and 0.75 (SD 0.27) for the high-dose session. Depressive symptoms were markedly reduced 1 week and 3 months after high-dose treatment, with a mean QIDS difference of -11.8 (95% CI -9.15 to -14.35, p=0.002) at 1 week and -9.2 (95% CI -5.69 to -12.71, p=0.003) at 3 months. Marked and sustained improvements in anxiety and anhedonia were also noted. The study provides preliminary support for the safety and efficacy of psilocybin for treatment-resistant depression and motivates further trials with more rigorous designs to better examine its therapeutic potential. Funding was provided by the Medical Research Council. The study was registered with ISRCTN, number ISRCTN14426797. The results suggest that psilocybin may be a promising treatment option for treatment-resistant depression, with a favourable toxicity profile and no association with compulsive drug-seeking behaviours. However, the study was a small-scale feasibility study with an open-label design, so strong inferences about the treatment's therapeutic efficacy cannot be made. Future research should address the role of psychological support and the potential influence of expectancy and suggestibility in psychedelic therapy. The findings suggest that psilocybin has a novel pharmacological action in comparison with currently available treatments for depression (i.e., 5-HT2A receptor agonism) and could constitute a useful addition to available therapies for the treatment of depression.This open-label feasibility study investigated the safety, feasibility, and efficacy of psilocybin with psychological support in patients with treatment-resistant depression. Twelve patients with moderate-to-severe, unipolar, treatment-resistant depression received two oral doses of psilocybin (10 mg and 25 mg, 7 days apart) in a supportive setting. The primary outcome measure for feasibility was patient-reported intensity of psilocybin's effects, while depressive symptoms were assessed using the 16-item Quick Inventory of Depressive Symptoms (QIDS). Psilocybin was well tolerated by all patients, with no serious or unexpected adverse events. The acute psychedelic effects of psilocybin typically became detectable 30–60 min after dosing, peaked 2–3 h after dosing, and subsided to negligible levels at least 6 h after dosing. The mean self-rated intensity of psilocybin experience was 0.51 (SD 0.36) for the low-dose session and 0.75 (SD 0.27) for the high-dose session. Depressive symptoms were markedly reduced 1 week and 3 months after high-dose treatment, with a mean QIDS difference of -11.8 (95% CI -9.15 to -14.35, p=0.002) at 1 week and -9.2 (95% CI -5.69 to -12.71, p=0.003) at 3 months. Marked and sustained improvements in anxiety and anhedonia were also noted. The study provides preliminary support for the safety and efficacy of psilocybin for treatment-resistant depression and motivates further trials with more rigorous designs to better examine its therapeutic potential. Funding was provided by the Medical Research Council. The study was registered with ISRCTN, number ISRCTN14426797. The results suggest that psilocybin may be a promising treatment option for treatment-resistant depression, with a favourable toxicity profile and no association with compulsive drug-seeking behaviours. However, the study was a small-scale feasibility study with an open-label design, so strong inferences about the treatment's therapeutic efficacy cannot be made. Future research should address the role of psychological support and the potential influence of expectancy and suggestibility in psychedelic therapy. The findings suggest that psilocybin has a novel pharmacological action in comparison with currently available treatments for depression (i.e., 5-HT2A receptor agonism) and could constitute a useful addition to available therapies for the treatment of depression.