Purpose 188Re-HEDP is indicated for the treatment of pain in patients with painful osteoblastic bone metastases, including hormone-refractory prostate cancer patients. Efficacy may be improved by adding chemotherapy to the treatment regimen as a radiation sensitizer. The combination of 188Re-HEDP and capecitabine (Xeloda®) was tested in a clinical phase I study. Methods Patients with hormone-refractory prostate cancer were treated with capecitabine for 14 days (oral twice daily in a dose escalation regimen with steps of 1/3 of 2,500 mg/m2 per day in cohorts of three to six patients, depending on toxicity). Two days later patients were treated with 37 MBq/kg 188Re-HEDP as an intravenous injection. Six hours after treatment post-therapy scintigraphy was performed. Urine was collected for 8 h post-injection. Follow-up was at least 8 weeks. The primary end-point was to establish the maximum tolerable dose (MTD) of capecitabine when combined with 188Re-HEDP. Secondary end-points included the effect of capecitabine on the biodistribution and pharmacokinetics of 188Re-HEDP. Results Three patients were treated in the first and second cohorts, each without unacceptable toxicity. One of six patients in the highest cohort experienced unacceptable toxicity (grade 4 thrombopaenia). The MTD proved to be the maximum dose of 2,500 mg/m2 per day capecitabine. No unexpected toxicity occurred. Capecitabine had no effect on uptake or excretion of 188Re-HEDP. Conclusion Capecitabine may be safely used in combination with 188Re-HEDP in a dose of 2,500 mg/m2 per day and 37 MBq/kg, respectively. Efficacy will be further studied in a phase II study using these dosages.