PurposeThis retrospective study aimed to assess the efficacy and safety of palliative radiotherapy for painful non-bone lesions in patients with advanced cancer.Materials and methodsWe enrolled patients with painful non-bone lesions who underwent conventional palliative radiotherapy between September 2018 and September 2022. The treatment targets included primary tumor lesions, lymph node metastases, non-bone hematogenous metastases, and other lesions. The primary endpoint was the overall pain response rate in evaluable patients, determined based on the International Consensus Pain Response Endpoint criteria. The secondary endpoints included overall survival, pain recurrence, and adverse events.ResultsOf the 420 screened patients, 142 received palliative radiotherapy for painful non-bone lesions, and 112 were evaluable. A pain response was achieved in 67 patients (60%) of the 112 evaluable patients within a median of 1.2 months. Among these patients, 25 exhibited complete response, 42 partial response, 18 indeterminate response, and 27 pain progression. The median survival time was 5.5 months, recorded at a median follow-up of 6.0 months, during which 67 patients died. Multivariate analysis identified poor performance status scores of 2–4, opioid use, and re-irradiation as independent factors associated with a reduced likelihood of achieving a pain response. Pain recurrence occurred in 18 patients over a median of 4.1 months. Seventeen patients had grade 1–2 adverse events, while none experienced grade 3 or higher toxicity.ConclusionPalliative radiotherapy can potentially be a safe and well-tolerated modality for managing painful non-bone lesions, with a low rate of adverse events.