Background: Depression and schizophrenia are the global common causes worldwide of long-term and devastating disability, which significantly impact the patient quality of life. This paper is aimed to analyze and compare the health-related quality of life (HRQOL) of patients with Depression and Schizophrenia, determine main impact factors of their HRQOL with these two diseases and try to distinct the difference of impacts at socio-demographic,socioeconomic and medical level. Methods: 204 out-patients and in-patients diagnosed Depression or Schizophrenia according to Chinese classification and diagnostic criteria of mental disorders (CCMD-3) were sampled, who were volunteering to participate and can understand the meaning of questionnaires with accordance of the included criteria. The Health survey questionnaire (SF-36) and self-administered measurements were used to appraisal the subjective health status, the disease characteristics and other relevant medical potential predictors of participants. Results: All of the domain scores of SF-36 of patients with Depression and Schizophrenia are both lower than healthy people and there are significant differences in all domains, compared with depression group, most domains of SF-36 in Schizophrenia group are lower besides the body pain (BP) and social function (SF), and are difference in domains of role physical (RP) and mental health (MH) between two patient groups. For depression group, the predictors of unmarried status, subject change of health status and depression degree are correlated to HRQOL in PCS, the predictors of unmarried status, ethnicity and duration of disease are correlated to HRQOL in MCS. For schizophrenia group, predictors of subjective change of health status, family annual income, educational level, severity degree and ethnicity are associated with HRQOL in PCS, only predictor of ethnicity is associated with HRQOL in MCS. Conclusion: The HRQOL of patients was likely be impacted by the factors at both socio-demographic and medical level, but the functions of the same factors were different between depression and schizophrenia.