Background Antalgic radiotherapy for bone metastases might be improved by implementing biological information in the radiotherapy planning using 18 F-FDG-PET-CT based dose painting by numbers (DPBN). Materials and methods Patients with uncomplicated painful bone metastases were randomized (1:1:1) and blinded to receive either 8 Gy in a single fraction with conventionally planned radiotherapy (arm A) or 8 Gy in a single fraction with DPBN (dose range between 610 Gy and 10 Gy) (arm B) or 16 Gy in a single fraction with DPBN (dose range between 1410 Gy and 18 Gy) (arm C). The primary endpoint was overall pain response at 1 month. The phase II trial was designed to select the experimental arm with sufficient promise of efficacy to continue to a phase III trial. Results Forty-five patients were randomized. Eight (53%), 12 (80%) and 9 patients (60%) had an overall response to treatment in arm A, B and C, respectively. The estimated odds ratio of overall response for arm B vs. A is 3.5 (95% CI: 0.44–17.71, p = 0.12). The estimated odds ratio of arm C vs. A is 1.31 (95% CI: 0.31–5.58, p = 0.71). Conclusion A single fraction of 8 Gy with DPBN will be further evaluated in a phase III-trial. [ABSTRACT FROM AUTHOR]