Background: This study compared the efficacy of two commonly used fractionation schedules for palliative whole brain irradiation in patients with brain metastases, and assessed the association of the Radiotherapy Therapy Oncology Group (RTOG) Recursive Partitioning Analysis for brain metastases (RPA) to survival with each schedule.Methods: Patients with multiple (more than three) brain metastases were assigned to receive whole brain irradiation in 20 Gy over 5 fractions (group 1) or 30 Gy over 10 fractions (group 2). Primary outcome was response and overall survival in each group. Secondary outcome was the RPA classification relation to overall survival and its possible role in the choice between schedules.Results: There were 54 patients in group 1 and 39 in group 2. There was no significant difference in response (P=0.67) or overall survival between the two groups (P=0.55). However RPA 1 patients had significantly better overall survival than RPA 2 patients in both group 1 (P=0.02) and group 2 (P=0.0014), but no significant difference was found when overall survival of RPA 1 patients of both groups were compared (P=0.47) or that of RPA 2 patients in both groups (P=0.29). Conclusion: The two schedules assessed are comparable in terms of response and overall survival. RPA 1 patients have better overall survival than RPA 2 patients regardless of the fractionation used. A schedule of 20 Gy over 5 fractions should be routinely considered for RPA 2 patients as they are less likely to experience late toxicity. This schedule may be considered for RPA 1 patients, however larger randomized trials are needed to confirm the results and assess differences in neurocognitive function.