Objectives: This prospective, randomized phase III study was initiated to compare the efficacy and side effects of bilateral orchiectomy versus a combination of a luteinizing hormone-releasing hormone agonist depot formulation, goserelin acetate (3.6 mg s.c. once every 4 weeks) and flutamide (250 mg 3× daily) in patients with metastatic prostate cancer. Methods: Relative treatment efficacy was assessed by comparing the two treatment groups with respect to response, time to first progression, progression-free survival, duration of survival and time to death due to malignant disease. Results: There was a difference in response only with respect to a more frequent decrease to normal of the serum prostate acid phosphatase in patients assigned to maximal androgen blockade treatment. Additionally, maximal androgen blockade treatment showed significantly better results for duration of survival (p = 0.04), time to death due to malignant disease (p = 0.008), time to first progression (p = 0.009) and progression-free survival (p = 0.02). The most frequent side effects for both treatments included hot flushes and gynaecomastia. Conclusions: Increased time to progression and duration of survival is achieved by the combination of flutamide and goserelin when compared to bilateral orchiectomy.