Objective To compare the effects of simplified cognitive behavioral therapy（ SCBT） combined with medication， supportive psychotherapy（ SP） combined with medication， and medication therapy alone on the quality of life in patients with major depressive disorder. Methods A randomized controlled trial design was adopted. A total of 120 patients with major depressive disorder were randomly divided into SCBT combined with medication group， SP combined with medication group and medication group. Eight weeks treatment and 12 weeks follow-up were carried out. The quality of life of patients was evaluated from 8 dimensions by health status questionnaire. Rusults Totals of 94 cases were included in the statistical analysis. The number of patients in the three groups were 34， 32 and 28. There were no statistically significant differences in sociodemographic factors， onset patterns， the progression of the disease， and the severity of depression among the three groups（ P ＞ 0.05）. At baseline， the differences of physical function， general health status， and social function were statistically significant（ P＜0.05） among the 3 groups and the score of medication group was lower. At the end of the intervention， the general health status score of SCBT combined with medication group was higher than that of the SP combined with medication group in（ F=3.695， P=0.026）， and the mental health score was higher than that of the medication group（ F=8.409， P＜ 0.05）. At the end of the 12 weeks， the physiological function score of the SCBT combined with medication group was higher than that of the medication group（ F=3.606， P=0.028）. The general health status score was higher than that of the SP combined with medication group（ F=4.762， P=0.009）. The scores of vitality dimension（ F=4.725，P=0.010） and mental health dimension（ F=12.066， P＜0.05） were higher than those of the other two groups. The results of comparison among groups showed that there were statistically significant differences in all 8 dimensions of the life quality in the SCBT combined with medication group（ P ＜ 0.05）. There were statistically significant differences in 3 out of 8 dimensions in the SP combined with medication group and the medication group（ P＜ 0.05）. Conclusions SCBT combined with medication therapy， SP combined with medication therapy and medication therapy alone can effectively improve the quality of life of patients with major depressive disorder. SCBT combined with medication therapy is more effective on improving physical function， general health status， vitality and mental health of patients with major depressive disorder.