We appreciate Drs. Thombs and Ziegelstein's observation that our study was of great importance in reporting the beneficial effect of a depression intervention on mortality. Drs. Thombs and Ziegelstein were concerned that the post hoc selection of covariates for inclusion only if they were associated with the outcome led to overfitting and ignored the issue of confounding. We had a prespecified approach to identifying and including potential confounders because we knew that imbalances would be likely and that adjustment with patient-level variables would be necessary given the practice-randomized design. Our prespecified approach did address the concern about confounding by identifying potential confounders for inclusion in the model by their association (P = 0.100) with the interaction variables of interest, randomization assignment, and baseline depression status, as well as the dependent variable, time to death. Using this approach, only age, level of educational attainment, baseline smoking status, history of myocardial infarction reported at baseline, and baseline suicidal ideation were identified as potential confounders. The intention-to-treat hazard ratio and corresponding 95% CI for patients with major depression was consistent with the reported result (adjusted hazard ratio, 0.62 [CI, 0.42 to 0.92]). Additional variables for which we adjusted the point estimates reported in Table 4 were requested by reviewers. We want to emphasize the prespecified nature of our statistical approach and the care with which we selected variables for inclusion in models. The surprising finding relating to a reduction in cancer deaths was unadjusted and therefore was not influenced by the selection of covariates in multivariate models. We stated that any "evidence of a potential association of practice intervention assignment and specific causes of death must be viewed as an opportunity for generation of hypotheses to be tested in future intervention research." We did not call for research on mechanisms related to the decreased mortality risk from cancer. On the other hand, we would not want to be dismissive of the findings with regard to cancer deaths. We did suggest that mediators of the effect of a depression intervention on mortality deserve further study to increase our understanding of how depression leads to increased mortality. We believe this is the first publication of a randomized clinical trial to report decreased mortality in association with treatment of depression. Replication would be welcome.