Background: Docetaxel is a lipophilic drugs with a high affinity for adipose tissue resulting in a higher volume of distribution.There are contradictory data with regards to the differential effect of docetaxel based on BMI in breast cancer patients. However, there are no such data in patients with prostate cancer. A We performed an exploratory analysis to determine if the benefit of docetaxel in patients with metastatic castration resistant prostate cancer (mCRPC) is modified by BMI. Methods: This is a post hoc analysis of data retrieved from the phase III ENTHUSE M1C study that assessed the efficacy and safety of additional zibotentan in combination with docetaxel in patients with mCRPC (ClinicalTrials.gov identifier: NCT00617669). BMI (kg/m2) was categorized as: 18.5 to < 25, lean; 25 to < 30, overweight; and ≥ 30, obese. Cox regression models were constructed to determine the impact of BMI on progression-free survival (PFS) and overall survival (OS) after adjusting for baseline characteristics. Results: A total of 466 patients were eligible for current analysis, of whom 34%, 46% and 20% were < 65 years, 65-74 years and > 75 years, respectively. The median total and free baseline PSA were 99.5 (interquartile range [IQR], 33.6 to 237.0) ng/mL and 13.9 (IQR, 5.4 to 37.4) ng/mL, respectively. There were 31% (n = 145), 46% (n = 213) and 23% (n = 108) lean, overweight and obese patients. Visceral metastasis was present in 52% patients, while the number of bone metastases were 1-3 in 15%, 4 in 5%, 5-20 in 58% and ≥ 21 in 23%. The median number of cycles of docetaxel administered were 10 (IQR, 6-10). The median PFS was 7.3, 7.7 and 8.4 months (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.81 to 1.06; P = .26) for lean, overweight and obese patients, respectively. The median OS was 10.3, 10.7 and 12.4 months (HR, 0.75; 95% CI, 0.63 to 0.89; P = .01) for lean, overweight and obese patients, respectively. After adjusting for baseline and tumor related characteristics, there was no association of BMI with PFS (overweight, HR, 0.92; 95% CI, 0.73 to 1.17; P = .50; obese, HR, 0.90; 95% CI, 0.67 to 1.18; P = .42) while overweight (HR, 0.68; 95% CI, 0.52 to 0.91; P = .01) and obese (HR, 0.61; 95% CI, 0.43 to 0.88; P = .01) patients had significantly better OS as compared with lean patients. Conclusions: The differential effect of docetaxel based on BMI was not observed in patients with mCRPC. Interestingly, obese patients had a significantly longer OS, which warrants further investigation.