This study evaluated extended release quetiapine fumarate (quetiapine XR) monotherapy in elderly patients with major depressive disorder (MDD) according to baseline levels of anxiety, sleep disturbance, and pain. Post-hoc analyses of data from an 11-week (9-week randomized-treatment, 2-week post-treatment phase), double-blind, placebo-controlled study of quetiapine XR (50–300 mg/day) monotherapy in elderly (≥66 years) patients (n=338) with MDD were carried out. Outcomes included randomization to week 9 change in Montgomery Åsberg Depression Rating Scale (MADRS) score and week 9 response (≥50% MADRS score reduction) rates. Post-hoc analyses were carried out to assess subgroups of patients with MDD according to baseline levels in terms of the following: higher or lower anxiety (Hamilton Rating Scale for Anxiety total score≥20 or < 20, respectively); high or low sleep disturbance [Hamilton Rating Scale for Depression sleep disturbance factor (items 4+5+6) score≥5 or <5, respectively]; and pain visual analog scale total score 40 mm or higher or less than 40 mm. At week 9, quetiapine XR reduced the MADRS total score compared with placebo in the higher anxiety (least squares mean change −17.8 vs. −8.5; P<0.001) and lower anxiety (−14.8 vs. −8.8; P<0.001) subgroups. MADRS total score was also reduced with quetiapine XR compared with placebo in the high (−17.6 vs. −8.7; P<0.001) and low (−14.4 vs. −9.2; P<0.001) sleep disturbance subgroups, as well as in the pain visual analog scale subgroups [≥40 mm (−16.6 vs. −8.9; P<0.001) and <40 mm (−15.7 vs. −8.7; P<0.001)]. Quetiapine XR response rates were higher than those of placebo in all subgroups analyzed. In this study, quetiapine XR (50–300 mg/day) monotherapy was shown to be effective against depressive symptoms in elderly patients with MDD, irrespective of baseline levels of anxiety, sleep disturbance, and pain.