Background: We explored whether clinical outcomes differ by treatment strategy following initial antidepressant treatment failure among patients with and without clinically relevant symptom clusters. Methods: The Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial was used to examine depression remission and response in patients with coexisting anxiety, atypical features, insomnia, and low energy. We applied propensity scoring to control for selection bias that precluded comparisons between augmentation and switch strategies in the original trial. Binomial regressions compared the likelihood of remission or response among patients with and without symptom clusters for switch versus augmentation strategies (n = 269 per arm); augmentation strategy type (n = 565); and switch strategy type (n = 727). Results: We found no statistically significant difference in remission or response rates between augmentation or switch strategies. However, symptom clusters did distinguish among augmentation and switch strategies, respectively. For patients with low energy, augmentation with buspirone was less likely to produce remission than augmentation with bupropion (remission Risk Ratio (RR): 0.54, 95% CI: 0.35–0.85, response RR: 0.67, 95% CI: 0.43, 1.03). Also, for patients with low energy, switching to venlafaxine or bupropion was less likely to produce remission than switching to sertraline (RR: 0.59, 95% CI: 0.36–0.97; RR: 0.63, 95% CI: 0.38–1.06, respectively). Conclusions: Remission and response rates following initial antidepressant treatment failure did not differ by treatment strategy for patients with coexisting atypical symptoms or insomnia. However, some second-step treatments for depression may be more effective than others in the presence of coexisting low energy. Subsequent prospective testing is necessary to confirm these initial findings. Depression and Anxiety, 2011. © 2011 Wiley Periodicals, Inc.