Background: This study was intended to evaluate the clinical effect of somatosensory interaction transcutaneous electrical acupoint stimulation (SI-TEAS) on cancer-related fatigue (CRF) and its safety.Methods: The study protocol had been registered in China Clinical Trial Registration Center with registration number: ChiCTR2100045655. CRF patients were equally divided into SI-TEAS Group, Acupressure Group and Sham Acupressure Group to receive SI-TEAS, acupressure and sham acupressure treatments 5 times a week. The fatigue levels of patients in the 3 groups were measured by the Piper Fatigue Scale during the baseline period and after 4 and 8 weeks (of treatment). The cell immunity of these patients was determined by detecting the T-lymphocyte subsets and NK cells.Result: Of the 300 participants, 279 have gone through the independent rehabilitation intervention study, including 94 in the SI-TEAS Group, 92 in the Acupressure Group, and 93 in the Sham Acupressure Group. Intergroup comparisons of fatigue degree and cell immunity, namely SI-TEAS Group versus Acupressure Group, Acupressure Group versus Sham Acupressure Group, and SI-TEAS Group versus Sham Acupressure Group, showed that group changes observed during the baseline period and different time points after Week 4 and 8 were statistically different (P < 0.05). The SI-TEAS Group had the sharpest decreases in the behavioral, sensory, emotional and cognitive dimensions of fatigue, and the total score, followed by the Acupressure Group, while the Sham Acupressure Group did not show significant changes; the SI-TEAS Group experienced the sharpest increases in the absolute counts of CD3 + T cells, CD4 + T cells, CD8 + T cells, CD4 + /CD8 + T cells, and NK cells, followed by the Acupressure Group, while the Sham Acupressure Group did not show significant changes.Conclusion: SI-TEAS could significantly relieve the fatigue of CRF patients and improve their cell immunity, which maybe a useful and effective option for reducing CRF in clinical practice.