OBJECTIVES: Approximately 1 in 5 adults in the U.S. experiences mental illness every year.  Despite the empirical literature demonstrating the efficacy of psychotherapeutic medications for a wide range of mental disorders, the patient’s overall well-being and quality of life still remain controversial. The study aims to investigate the effect of psychopharmacotherapy on patient reported health-related quality of life (HRQOL). METHODS: A retrospective cohort study was conducted by analyzing the Medical Expenditure Panel Survey (MEPS) longitudinal data 2012-13.  Adults with a diagnosis of mental disorder were identified using the clinical classification codes (CCS 640-670).  The Multum drug database was used to identify psychotherapy medications in four categories: antidepressants, antipsychotics, anxiolytics/sedatives, and CNS stimulants.  Univariate quantile-quantile (Q-Q) plots and kernel density estimations (KDE) were performed to assess the normality of HRQOL scores.  Repeated t-tests were used to examine the effect of psychopharmacotherapy on patients’ quality of life.  HRQOL was measured using the SF-12 Physical (PCS) and Mental (MCS) Component Summary.  All analyses utilized SAS PROC SURVEY applications and incorporated sample weights and standard errors to adjust the complex sampling design. RESULTS: An Estimated 46.5 million adult patients were diagnosed with mental disorder in two consecutive years 2012-13. Females accounted for a much higher prevalence than males (62% vs. 38%).  12.3 million (26.5%) patients received at least one antipsychotherapeutic agent.  The results from Q-Q plots and KDE showed a normal distribution of each outcome measure. The adjusted difference in HRQOL among patients with psychopharmacotherapy and those without it showed no significant difference in both PCS (P=0.48) and MCS (P=0.58). The adjusted association between each antipsychotherapeutic category and its MCS/PCS also showed no significant difference.  CONCLUSIONS: The effect of psychopharmacotherapy on HRQOL were small and no statistically significant. These findings suggest that the choice of medication and/or psychotherapy could be critical to a patient’s overall quality of life.