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Purpose: The purpose of this study was to investigate the effect of a comprehensive rehabilitation program on physical function, immune response, fatigue and quality of life in mastectomy patients. Method: The subjects included fifty-five patients with breast cancer (27 in the control group and 28 in the experimental group). The subjects in the experimental group participated in a comprehensive rehabilitation program for10 weeks, which was composed of 1 session of education, 2 sessions of stress management, 2 sessions of exercise, and 1 session of peer support group activity per week. Result: The results revealed anincrease in shoulder extension, abduction, external rotation, and internal rotation of the affectedupper extremity, and in shoulder extension and abduction of the healthy upper extremity. Also an increase in quality of life and a decrease in fatigue were significantly higher in the experimental group than the control group. However, the results revealed that the natural killer cell ratio of the experimental group increased but there was no significant difference from that of the control group. Conclusion: The 10-week comprehensive rehabilitation program showed a large affirmative effect on physical function, fatigue and quality of life of breast cancer patients after a mastectomy.