Strontium-89 is an established alternative for the alleviation of bone pain in prostate cancer. There are few data evaluating the effect on pain of palliative chemotherapy. The aim of this randomized phase II study was to assess and compare the analgesic efficacy of strontium-89 and chemotherapy (FEM=5-FU, epirubicin, and mitomycin C) in 35 patients with disseminated, hormone-refractory prostate cancer suffering from persisting bone pain despite analgesic treatment. In order to minimize the risk for imbalances regarding the two patient groups, a double-blind randomization was performed. A significant reduction in pain intensity and pain frequency was registered in both patient groups (P < 0.01 in both groups after 3 weeks). Side effects were generally mild in the strontium-89 group and significantly more severe in the FEM group. The effect of FEM on pain is surprising as chemotherapy has generally only limited effect on tumor growth in bone metastases due to prostate cancer. A possible explanation is that FEM has an inhibitory activity on the inflammatory component of metastases.