OBJECTIVES: The adjunctive use of some atypical antipsychotics (AAPs) has shown to provide some benefits in improving the depressive symptoms in patients with treatment-resistant depression. However, little is known about the impact of these agents on patients’ health-related quality of life (HRQoL). METHODS: Patients with self-reported depression (ICD-9: 296, 300, and 311), and have used the given AAPs and/or antidepressants for at least a year, were identified in the Medical Expenditure Panel Survey (MEPS) of 2008-2011. The patients were classified into users of adjunctive AAPs (i.e., antidepressants plus AAPs) and users of antidepressants only. The AAPs were identified based on documented evidence, and included risperidone, aripiprazole, quetiapine, olanzapine, and ziprasidone. Multivariate linear regression analyses were conducted to determine whether the utilization of AAPs was associated with the Physical Component Summary-12 (PCS12) or with Mental Component Summary-12 (MCS-12) of HRQoL measure. Socio-demographics, Charlson Comorbidity Index, psychotherapy (i.e., cognitive behavioral therapy), Patient Health Questionniare-2 (PHQ-2) scores, and the number of prescription medications associated with depression were controlled. RESULTS: A total of 3,638 participants reported to have depression and to have used the given AAPs and/or antidepressants for at least a year during the period of 2008-2011 (306 on AAPs vs. 3,332 on antidepressants only). The study subjects were ≥18 years, predominately White (91.9%) and female (71%). The adjunctive AAPs utilization was not associated with higher scores in the PCS-12 (β = 1.455, 95% CI = − 0.1366-3.0459, p =0.0729). Rather, it was negatively associated with the MCS-12 scores (β = − 1.549, 95% CI = − 3.0171-− 0.0822, p =0.0386). CONCLUSIONS: The adjunctive utilization of AAPs was not associated with higher scores of HRQoL. Future studies should examine whether poor mental scores of HRQoL have occurred from lower medication adherence to AAPs or from lower baseline HRQoL scores among users of adjunctive AAPs.