Abstract: OBJECTIVE This study focused on the verification of the the TCM Qi-defiency syndrome and depression-like behavior in Balb/c mice following chronic unpredictable mild stress (CUMS)， and the underlying molecular biology of disease-syndrome association. METHODS CUMS was used to induce depression on the female Balb/c mice. Sijunzi Decoction (SJZD) was administrated to mice and the syndromes were verified based on pharmacological effect. We assessed the behaviors of depression in the mice by open field test (OFT)， sucrose preference test (SPT) and novelty suppressed feeding (NSF). We assessed the Qi-deficiency phenotype by exhausted swim test， degree of redness， grip strength and fur condition. The changes of PKA-CREB signaling in muscle and hippocampus of mice were observed via Western blot. RESULTS SJZD improved Qi-deficiency like syndromes of Balb/c mice by reversing deficits in grip strength， exhausted swim test and increased fur score. SJZD also reversed depressive like behaviors by increasing the sucrose preference and so on. The decreased phosphorylation of the CREB (p-CREB) and PKA expression of hippocampus and muscle in CUMS mice were reversed by SJZD. CONCLUSION Follwing CUMS， Balb/c mice displayed depression-like behavior and Qi deficiency-like syndromes， both of which were rescued by using the Qi-tonifying formula SJZD. Improving PKA-CREB signaling in periphery and brain may be an essential mechanism. The findings supported the susceptibility to the Qi-deficiency syndrome of Balb/c mouse strain， and the validality of TCM treatment of diseases based on syndrome.