Background: Androgen deprivation therapy induces osteosarcopenia, which in turn is associated with prostate cancer related morbidity, mortality and health expenditures. Although bone and skeletal muscle health are interconnected at multiple levels, clinical guidelines focus on the prevention and management of osteoporosis while largely ignoring skeletal muscle health. Due to the paucity of studies investigating the impact of A or E therapy on skeletal muscle loss, we decided to compare the effects of the two agents on sarcopenia development among men with mCRPC. Methods: In this retrospective single-centre study we identified a total of 58 mCRPC patients (pts) who (i) had received treatment with A (n = 29) or E (n = 29) for > 1.5 years, (ii) had an available routine abdominopelvic CT scan at baseline, and (iii) had at least one follow-up CT scan 12 and/or 24 months after treatment initiation. Using the contour tool of the eUnity imaging platform, we obtained the total contour area of the left and right psoas muscle at the inferior endplate of L3 in order to calculate the Psoas Muscle Index (PMI; defined as the total contour area divided by patients’ height in meters) as a measure of sarcopenia. Results: The median age of men undergoing A or E therapy was 75 (range 70-79) versus 69 (67-75) years (p = 0.09), with A use for first line mCRPC therapy in 65.5% of pts, and of E in 69.0% of pts. The median time on A was 30.3 (95%CI 27.2-46.0) months, compared to 42.8 (27.4-49.9) months for men on E (p = 0.96). Using a PMI cut-off for sarcopenia of < 5.7, the rate of sarcopenia increased from 34.5% at baseline to 39.3% at 24 months in pts undergoing A therapy (p = 0.71); the median PMI of A pts at baseline was 6.79 (95%CI 5.48-7.22) and steadily decreased to 5.86 (5.46-6.42) at 24 months (p = 0.0002). As for E, the rate of sarcopenia increased from 24.1% to 39.3% after 24 months of treatment (p = 0.21), with a concurrent PMI decrease from 6.73 (95%CI 5.87-7.64) to 6.32 (5.25-6.90; p = 0.001). There were no significant PMI differences between the A and E cohorts at baseline, month 12, or month 24. Furthermore, the presence versus absence of baseline sarcopenia was not significantly associated with the time on A or E therapy (p = 0.15 and p = 0.54, respectively). Conclusions: A sizeable number of men with mCRPC are sarcopenic at start of A or E therapy. In addition, the use of both agents is associated with an increase in the rate of sarcopenia, and with significant PMI decreases over time. The sarcopenia-inducing potential of A and E is comparable, while baseline sarcopenia seems not to predict time on A or E.