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Objectives The aim of this study is to establish Korean pharmacological treatment guidelines for the initial choice of antidepressant for treatment of moderate or severe depression. Methods The process for establishment of guidelines involved determination of important key questions, selection of 12 international and domestic clinical practice guidelines for depression,drawing of recommendation drafts, and peer review. Results Selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), norepinephrine-dopamine reuptake inhibitors (NDRI), and noradrenergic and specific serotonergic antidepressants (NaSSA) were strongly recommended as the first?line antidepressants for treatment of moderate or severe depression. SSRIs were weakly recommended for patients who had problems with tolerability. Consideration of not only efficacy but also provisional adverse effects, drug-drug interactions, history of treatment response, preference, acceptability, cost, comorbid illnesses, and other factors in the choice of first-line antidepressants was strongly recommended. The treatment recommendations for specific clinical features of depression were as follows. SSRIs were weakly recommended for atypical depression. Augmented use of antipsychotics to antidepressants was strongly recommended for psychotic depression. Bupropion and SSRIs were weakly recommended for seasonal depression. Conclusion The results of this study may contribute toward improving the quality of depression treatment by providing clear and definite recommendations for the initial choice of antidepressant for treatment of moderate or severe depression.This study was supported by a grant of the Korean Health 21 Care Technology R & D Project, Ministry of Health and Welfare, Republic of Korea (A102065)