IMPORTANCE: Preclinical evidence and case reports suggest potential therapeutic benefits of ketogenic diets (KDs) in the treatment of depression, but evidence from well-controlled randomized clinical trials (RCTs) is lacking. OBJECTIVE: To assess the efficacy of a KD compared with a control diet in adults with treatment-resistant depression (TRD). DESIGN, SETTING, AND PARTICIPANTS: This RCT was conducted between February 22 and June 15, 2024. Participants aged 18 to 65 years with TRD and a score of 15 or greater on the 9-item Patient Health Questionnaire (PHQ-9) from across the UK were included. INTERVENTION: Participants were randomized 1:1 to one of two 6-week dietary interventions: (1) KD of prepared foods providing less than 30 g of carbohydrates per day with weekly individual dietetic support or (2) a control (phytochemical [phyto]) diet with vouchers to purchase 1 extra serving of vegetables or fruit and replace saturated fats with unsaturated fats, with equal dietetic support. The last follow-up was at 12 weeks. MAIN OUTCOMES AND MEASURES: The primary outcome was the between-group difference in change in PHQ-9 score from baseline to week 6. Secondary outcomes included PHQ-9 score at 12 weeks, depression remission, anxiety, anhedonia, cognitive impairment, quality of life, and functional outcomes. RESULTS: The study included 88 participants (mean [SD] age, 42.1 [13.1] years; 61 women [69%]): 44 in the KD group and 44 in the phyto diet group. Depression severity decreased markedly in both groups; the mean (SD) change in PHQ-9 score from baseline to week 6 was -10.5 (7.0) in the KD group and -8.3 (5.1) in the phyto group. The mean between-group differences in PHQ-9 score at 6 and 12 weeks were -2.18 (95% CI, -4.33 to -0.03; P = .05; Cohen d, -0.68; 95% CI -1.35 to -0.01) and -1.85 (95% CI, -4.04 to 0.33; P = .10; Cohen d, -0.58; 95% CI, -1.26 to 0.10), respectively. There were no differences in secondary outcomes between the KD and phyto groups. No serious adverse events occurred. CONCLUSIONS AND RELEVANCE: In this RCT, a KD had antidepressant benefits compared with a well-matched control diet at 6 weeks. However, the clinical relevance is uncertain, as the mean effect size compared with the control was modest and not evident in secondary analyses. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06091163.