Despite advances in the multimodal approach for rectal cancer, treatment-related side effects remain an important issue. From this perspective, a prospective trial was performed to investigate the feasibility of modulated electro-hyperthermia (mEHT) as a concomitant boost to preoperative chemoradiation in locally advanced rectal cancer. Seventy-six patients with cT3-4 or cT2N+ rectal cancer were enrolled consecutively. Whole pelvic radiotherapy of 40 Gy was delivered with a 2-Gy daily fraction. mEHT with 13.56 MHz frequency was boosted on a twice-weekly schedule concurrently with intravenous 5-fluorouracil or oral capecitabine. Surgical resection was planned 6-8 weeks after radiotherapy. The primary endpoint was the non-inferior treatment response rate assessed by pathologic downstaging and tumor regression. The secondary endpoint was acceptable toxicity during the preoperative treatment period. Sixty patients completed the planned treatment schedule. T- and N-downstaging was demonstrated in 40 patients (66.7%) and 53 patients (88.3%), respectively. Pathologic complete response was noted in 15.0% (9 patients) and 76.7% (46 patients) for T-stage and N-stage, respectively. Total or near total tumor regression was observed in 20 patients (33.3%). Grade ≥3 toxicity occurred only in hematologic assessment; one case (1.7%) of leukopenia and one case (1.7%) of anemia. Sixteen patients (26.7%) developed thermal toxicity, which was mostly Grade 1 (15 patients, 93.8%). The relatively low dose of 40 Gy radiation showed comparable pathologic treatment outcomes and tolerable toxicity profiles with the addition of mEHT, which may potentially replace part of the radiation dose in neoadjuvant treatment for rectal cancer.