BACKGROUND: The presence of Major Depressive Disorder (MDD) is often comorbid in patients with a variety of general medical conditions (GMCs) which could lead to less favorable outcomes. OBJECTIVE: The goal of this analysis is to examine functional outcomes of QOL and functioning before and after antidepressant treatment among patients with MDD with and without GMCs. METHODS: We performed a secondary analysis based on the STAR*D database. The analysis included two patient groups from the STAR*D trial: 1,198 patients comorbid with MDD and GMCs (MDD + GMC) and 1,082 patients with MDD and no GMCs (MDDnoGMC), as defined by the Cumulative Illness Rating Scale. We analyzed depressive symptom severity, functioning and quality of life (QOL) before and after level 1 treatment with citalopram. RESULTS: At baseline, the MDD + GMC group had significantly lower QOL (p < 0.001) and functioning (p = 0.001) than the MDDnoGMC group, although depressive symptom severity was not significantly different. Following antidepressant treatment, QOL, functioning and depressive symptom severity significantly improved for both MDD + GMC and MDDnoGMC groups. However, patients with MDD + GMC were more likely to experience severe impairments in QOL in (56.8% vs. 43.5% for MDDnoGMC, p < 0.001) and functioning (42.5% vs. 29.3% for MDDnoGMC, p < 0.001) following treatment. The remission rate was significantly lower for MDD + GMC (30.6% vs. 41.1% for MDDnoGMC, p < 0.001). CONCLUSIONS: Our findings suggest that antidepressant treatment had a positive impact on patients with and without GMCs. However, those with GMCs experienced not only a lower remission rate, but also continued to experience more significantly severe impairments in QOL and functioning.