Abstract：Objective：To observe the clinical effect of Sijunzi Decoction on chronic fatigue syndrome of spleen deficiency type. Methods： A total of 72 cases of patients with chronic fatigue syndrome of spleen deficiency type were selected as the research subjects，and were divided into the control group and the trial group according to the random number table method，with 36 cases in each group. Both groups received health education. The trial group was treated with granules of Sijunzi Decoction， and the control group was treated with placebo granules. The clinical effects and safety were compared between the two groups. The fatigue symptom scores， traditional Chinese medicine (TCM) syndrome scores， fatigue degree [Chalder Fatigue Scale (Chalder) scores]， Chinese Version of Short Form Health Survey (SF-36) scores， EuroQol 5 Dimension 5 Level (EQ-5D-5L) scores and levels of serum oxidative stress indicators [cortisol， malondialdehyde (MDA)， superoxide dismutase (SOD)， and glutathione peroxidase (GSH-PX)] were compared before and after treatment. Results：After treatment，the total effective rate was 94.44% in the trial group，and 77.78% in the control group，the difference being significant (P＜0.05). After 1 and 2 months of treatment，the scores of fatigue symptoms such as sleep disorders，tension and anxiety，and memory decline in the two groups were decreased when compared with those before treatment (P＜0.05)，and the three scores in the trial group were lower than those in the control group at the same time point (P＜0.05). After 1 and 2 months of treatment， TCM syndrome scores and Chalder scores in the two groups were decreased when compared with those before treatment (P＜0.05)，and TCM syndrome scores and Chalder scores in the trial group were lower than those in the control group at the same time point (P＜0.05). After 1 and 2 months of treatment，the scores of SF-36 and EQ-VAS in the two groups were increased when compared with those before treatment (P＜0.05)；the above two scores in the trial group were higher than those in the control group at the same time point (P＜0.05). After 1 and 2 months of treatment，the serum levels of CORT，SOD，and GSH-PX in the two groups were increased when compared with those before treatment (P＜0.05)，and MDA levels were decreased when compared with those before treatment (P＜ 0.05)； the levels of CORT， SOD， and GSH-PX in the trial group were higher than those in the control group at the same time point (P＜0.05)，and MDA level was lower than that in the control group at the same time point (P＜0.05). Conclusion： Sijunzi Decoction has a significant curative effect in treating chronic fatigue syndrome of spleen deficiency type. It can improve symptoms such as spleen deficiency，improve the quality of life of patients，improve oxidative stress reactions，and has good safety.