OBJECTIVE To observe the preventive and therapeutic effect of Ganoderma lucidum spore powder on cancer-related fatigue in postoperative adjuvant chemotherapy patients with breast cancer, and to provide a basis for using traditional Chinese medicine processed by modern processing to effectively improve the quality of life of cancer patients. METHODS Seventy-four female patients who received postoperative adjuvant chemotherapy for breast cancer in Zhejiang Cancer Hospital from November 2021 to March 2023 were randomly divided into either treatment(n=37) or control group(n=37). Both groups were given 4 cycles of epirubicin(or liposomal doxorubicin) combined with cyclophosphamide adjuvant chemotherapy and corresponding symptomatic treatment: the treatment group was treated with sporoderm-removed Ganoderma lucidum spore powder 2 g·d–1, and the control group was treated with placebo. The incidence and severity of cancer-related fatigue, the changes in T lymphocyte subsets, serum inflammatory factors, intestinal flora, and the effects of drugs on blood routine, liver, and kidney function were compared between the two groups after treatment. RESULTS The incidence of cancer-related fatigue and the score of the Piper correction scale in the treatment group were significantly lower than those in the control group(P<0.05), the proportion of CD3+, CD4+, and CD3-CD56+ was significantly higher than that in the control group(P<0.05), while the proportion of CD8+ was significantly lower than that in the control group(P<0.05). The counts of IL-2 and IL-10 were higher than those in the control group, while the counts of IL-6, IL-8, and CRP were lower than those in the control group(P<0.05). The counts of leukocytes, neutrophils, and platelets in the control group were significantly higher than those in the control group(P<0.05), and the abundance of intestinal microflora in the control group was higher than that in the control group. There was no significant difference in liver and kidney function between the 2 groups. CONCLUSION Sporoderm-removed Ganoderma lucidum spore powder can significantly reduce the incidence and level of cancer-related fatigue in breast cancer patients during adjuvant chemotherapy, inhibit inflammatory factors, regulate intestinal flora and body immunity.