Background: Obesity is associated with aggressive prostate cancer. To explore whether weight loss favourably affects tumour biology and other outcomes, we undertook a presurgical trial among overweight and obese men with prostate cancer. Methods: This single-blinded, two-arm randomised controlled trial explored outcomes of a presurgical weight loss intervention (WLI) that promoted ∼ 1 kg per week loss via caloric restriction and increased physical activity (PA). Forty overweight/obese men with clinically confirmed prostate cancer were randomised to the WLI presurgery or to a control arm; changes in weight, body composition, quality-oflife, circulating biomarkers, gene expression, and immunohistochemical markers in tumour and benign prostatic tissue were evaluated. Results: The study period averaged 50 days. Mean (s.d.) change scores for the WLI vs control arms were as follows: weight: -4.7 (3.1) kg vs -2.2 (4.4) kg (P = 0.0508); caloric intake: -500 (636) vs -159 (600) kcal per day (P = 0.0034); PA: +0.9 (3.1) vs +1.7 (4.6) MET-hours per day (NS); vitality: +5.3 (7.14) vs -1.8 (8.1) (P = 0.0491); testosterone: +55.1 (86.0) vs -48.3 (203.7) ng dl-1 ( P= 0.0418); sex hormone-binding globulin: +14.0 (14.6) vs +1.8 (7.6) nmol l-1 (P = 0.0023); and leptin: -2.16 (2.6) vs -0.03 (3.75) (P = 0.0355). Follow-up Ki67 was significantly higher in WLI vs control arms; median (interquartile range): 5.0 (2.5,10.0) vs 0.0 (0.0,2.5) (P = 0.0061) and several genes were upregulated, for example, CTSL, GSK3B, MED12, and LAMC2. Conclusions: Intentional weight loss shows mixed effects on circulating biomarkers, tumour gene expression, and proliferative markers. More study is needed before recommending weight loss, in particular rapid weight loss, among men with prostate cancer.