Background: Docetaxel plus prednisone is a standard treatment for castration-resistant prostate cancer. Cyclophosphamide may be an effective combination partner. Methods: This randomised, multicentre, phase II trial compared the combination therapy of docetaxel plus prednisone plus cyclophosphamide with the standard therapy of docetaxel plus prednisone. Results: Thirty-three patients received six 3-week treatment cycles (in total 171 cycles). During treatment, an adequate decline in prostate-specific antigen was seen in both groups (p = 0.068) without between-group differences (p = 0.683). No relevant differences between within-group changes were observed for blood pressure, weight, pain score, laboratory variables or quality of life. There were no serious side effects apart from leucopenia requiring treatment (docetaxel + prednisone + cyclophosphamide arm) and no drug-related withdrawals; all three fatalities were considered to be cancer related. Conclusions: The oncological effectiveness and tolerability of docetaxel plus prednisone were supported; an additional effect of cyclophosphamide was not detected. However, the small number of patients and short observation period restrict the generalisability of the results.