Background: Several meta- or mega-analyses suggest antidepressant medications should be given only to severely depressed patients. In our experience, mild depression benefits from medication. We reanalyzed 1 clinic's randomized placebo-controlled antidepressant studies, limiting analyses to patients with major depressive disorder (MDD) without severe illness, to determine whether nonsevere depression responds to antidepressant medication. Data Sources: Archives of the Depression Evaluation Service outpatient clinic of the New York State Psychiatric Institute were searched for randomized, placebo-controlled antidepressant studies that were conducted between 1977 and 2009 and included patients having MDD and pretreatment Hamilton Depression Rating Scale (HDRS) scores <23. Study Selection: Six placebo-controlled studies were found, including 8 active treatment arms and 1,440 patients. 825 patients were randomized and had MDD and an HDRS score <23. DSM-III, DSM-III-R, or DSM-IV diagnostic criteria contemporary to each study were employed. Data Extraction:Treatments were compared within study and via a patient-level meta-analysis using analysis of covariance (ANCOVA) of HDRS end point scores adjusted for pretreatment score. The number needed to treat (NNT) was calculated from remission rates (HDRS end point score <= 7), which were compared by X-2. Effect sizes were calculated from change in HDRS scores. Secondary analyses investigated the effect of chronicity and atypical features on treatment response. Data Synthesis: Three of 6 studies showed significant (P<.001) treatment effects by ANCOVA, and 4 of 6 studies showed significant (P<.04) differences in remission. The NNT ranged from 3 to 8. Effect sizes ranged from -0.04 to 0.8, with 4 of 8 greater than 0.4. The patient-level meta-analysis confirmed these results; neither chronicity nor atypical features significantly affected outcome. Secondary analyses utilizing global ratings and self-report mimicked the main findings. Conclusions: Several studies demonstrated significant antidepressant efficacy for patients having nonsevere MDD. Efficacy was not trivial, as NNT ranged from 3 to 8, a range accepted by researchers as sufficiently robust to recommend treatment. These findings suggest mild-moderate MDD can benefit from antidepressants, contrary to findings by several other meta- or mega-analyses. J Clin Psychiatry 2012;73(4):518-525 (C) Copyright 2011 Physicians Postgraduate Press, Inc.