BackgroundSuperficial soft tissue metastasis (S-STM) of malignant tumors is uncommon and often brings great pain to patients. However, current treatment options are limited. The purpose of this study was to explore the clinical efficacy and prognostic factors of CT-guided radioactive iodine-125 (125I) seed implantation (RISI) for the treatment of S-STM.MethodsWe retrospectively evaluated 132 patients with S-STM who received RISI between June 2010 and July 2022. Local tumor progression-free survival (ltPFS), tumor response, pain control and complication were analyzed. The independent factors affecting ltPFS were screened out using a layered Cox proportional hazards model.ResultsThe median follow-up time was 8.3 months (interquartile range [IQR], 4.5–15.3 months). The objective response rate (ORR) was 81.8%. The median ltPFS was 9.1 (95% CI: 6.6, 11.6) months. The Cox proportional hazard regression model revealed that the independent factors influencing ltPFS included KPS score, primary tumor, metastases, boundary, density and postoperative D90 (All P < 0.05). After RISI, the rate of pain relief was 92.3%. 66 (84.6%) patients reported pain marked relief, and 6 (7.7%) experienced pain moderate relief. No severe adverse events associated with RISI were observed during follow-up.ConclusionsCT-guided RISI was associated with high local control and pain relief without severe adverse events and should be considered as a reliable palliative treatment modality for S-STM.Trial registrationTrial registration Retrospectively registered.