Objective To study the effect of acupuncture on alleviating side effect of paroxetine and improving quality of life in treating mild or moderate depression. Methods A randomized controlled clinical trial was performed. Inpatients and outpatients with depression (n=72) were randomly divided into electro-acupuncture(EA) and paroxetine group (group A, n=23), manual acupuncture and paroxetine group (group B, n=32) and paroxetine alone group (group C, n=17). Outcome was assessed with Hamilton depression scale(HAMD) at baseline and weeks 1, 2, 4, and 6. Side effects were assessed with rating scale for side effects(SERS) at baseline and weeks 2, 4, and 6.The world health organization quality of life(WHOQOL-BREF) scale on quality of life was given at baseline and week 6. Results There were no differences among the three groups at baseline (P>0.05). According to the HAMD scores, significant difference was seen between group A and C (Z=3.2242, P 0.05). SERS scores in the acupuncture groups were significantly lower than those for paroxetine alone at weeks 2(F=5.48, P<0.05), week 4(F=7.70, P<0.05), and week 6 (F=7.73, P<0.05). WHOQOL-BREF scores were significantly higher in the two acupuncture groups than those in the paroxetine only group in five periods, which were total subjective feelings regarding quality of life(F=4.19, P<0.05), health sensation(F=4.49, P<0.05), physical condition(F=12.46, P<0.05), psychology condition(F=10.52, P<0.05) and circumstances(F=5.36, P<0.05). Conclusion Acupuncture can alleviate side effect of paroxetine and improve quality of life in treating mild or moderate depression. Key words: Depression; Acupuncture treatment; Side effect; Quality of life