OBJECTIVES: Examine the association between residual symptoms of depression (depressive symptoms still present after 3 months of antidepressant treatment) and patient reported mental and physical quality of life.  METHODS: A subset of patients from the 2012 National Health and Wellness survey (n = 71,157), an annual general health survey of US adults, was used in this analysis. Inclusion criteria were a diagnosis of depression and treatment with an antidepressant medication for at least 3 months (n = 5,354). Residual symptoms were measured via the 9-item Personal Health Questionnaire (PHQ-9) depression scale and quality of life was measured via the SF-36v2 mental and physical component summary scores (MCS and PCS). Inter-relationships among symptoms were assessed using Pearson correlations, and Ordinary Least Squares (OLS) regression was used for MCS and PCS analyses.  RESULTS: The most common residual symptoms were fatigue (49.6%; “Feeling tired or having little energy”) and sleep problems (42.8%; “Trouble falling or staying asleep, or sleeping too much”). All residual symptoms were more strongly correlated with MCS scores (r = -.37 to -.60) compared with PCS scores (r = -.06 to -.26) (p<.01). In the OLS regression models, anhedonia (“Little interest or pleasure in doing things”) and sadness (“Feeling down, depressed, or hopeless”) held the strongest associations with lower MCS scores (p<.001), whereas fatigue held the strongest association with lower PCS scores (p<.001) after controlling for other residual symptoms.  CONCLUSIONS: Residual symptoms of depression persist despite adequate duration of antidepressant treatment and are associated with poorer quality of life.  Anhedonia and sadness were most strongly associated with lower mental quality of life while fatigue was most strongly associated with lower physical quality of life.