Background: Colorectal cancer (CRC) is the second leading cause of death in adults. Standard treatment for metastatic disease includes chemotherapy and biological agents. Although more than 50% of patients respond to multi agent chemotherapy, resistance to treatment is a significant problem and more than 85 % of patients die within five years. Radiofrequency hyperthermia (Oncothermia- OT) is a non-invasive treatment modality which utilizes 13 MHz external radiofrequency waves to selectively heat cancer cells to 45 C, contributing to apoptosis, and aggregation of DNA repair enzymes, potentially overcoming resistance and improving chemotherapy efficacy. It has been used alone or in combination with chemotherapy. Since most metastatic CRC patients have disease limited to the abdominal cavity and liver, Oncothermia can be applied with a single electrode covering the entire abdominal cavity, immediately following chemotherapy without additional side effects. Methods: We treated 25 consecutive CRC patients with disease limited to liver and/or abdominal cavity with chemotherapy and biological agents and concomitant weekly OT (Oncotherm-EHY 3010) for one hour to the whole abdomen. Chemotherapy was FOLFIRI in 2, FOLFOX in 6, FOLFIRINOX in 17. Bevacizumab was used with chemotherapy in 22 and cetuximab in 1 patient. Patients were followed by periodic CT/MRI/PET-CT. Treatment duration ranged from 4 to 60 months. Results: No unexpected or grade III-IV toxicity was observed. Complete response was observed in 3 patients, partial response in 21 patients and stable disease in one patient for an objective response rate of 96%. Median follow up is 20.1 months (range 4-82+ months). 16 patients are alive, 3 with no disease and 13 on treatment. 9 patients have died. Conclusions: Although this is a single center retrospective observation, the combination of chemotherapy with Oncothermia appears tolerable and feasible in metastatic CRC. Despite the limitations of this observation, activity of this multi-modality treatment appears promising. Prospective randomized trials are needed to confirm these findings.