Objective: To investigate the clinical efficacy and mechanism of action of Shenmai injection for cancer related fatigue (CRF), Method: According to the clinical application of Shenmai injection, one hundred and fifty-six patients with CRF were divided into 86 cases of the observation group and 70 cases of the control group. The control group was treated by only conventional symptomatic treatment, while the observation group was treated by Shenmai injection in addition to conventional symptomatic treatment. The treatment in two groups lasted for 4 weeks. Piper fatigue revised scale, the indicators of quality of life scale, the syndrome score in traditional Chinese medicine and the immune function were evaluated. Result: The observation group showed a decrease in the number of CRF patients compared with the control group (P<0.01). The physical function, emotional function, social function and total score ratings in observation group were better than those in the control group (P<0.01). In observation group, levels of IgG, IgA, and IgM were higher than those in the control group, levels of IL-1 and TNF-α is were lower than those in the control group (P<0.05, P<0.01). The score of deficiency of qi and yin in the observation group was lower than that in the control group (P<0.01). Conclusion: Shenmai injection can improve immune function and reduce the score of deficiency of qi and yin, therefore it alleviates CRF and improve the quality of life.