Second-generation antidepressants dominate the management of patients with major depressive disorder (MDD). Evidence on the general and comparative benefits and harms is still accruing. To systematically review the general and comparative efficacy and safety of duloxetine for the treatment of acute-phase MDD in adults. We conducted a search of MEDLINE, Embase, PsychLit, The Cochrane Library, and the International Pharmaceutical Abstracts from 1980 to July 2009, as well as manually searching reference lists of pertinent review articles and exploring the Center for Drug Evaluation and Research database to identify unpublished research. For efficacy, randomized controlled trials (RCTs) comparing duloxetine with placebo or second-generation antidepressants were included. For safety, both experimental and observational studies were eligible. Abstracts and full-text articles were independently reviewed by two people, one investigator extracted relevant data, and a senior reviewer checked data for completeness and accuracy. We included 36 experimental and observational studies and, where sufficient data were available, meta-analyses of RCTs were conducted. Findings indicated that duloxetine is an effective treatment option for acute-phase MDD, with a tolerability profile similar to other second-generation antidepressants. No substantial differences in efficacy and safety appear to exist when duloxetine is compared with other second-generation antidepressants. Overall, about 40% of patients treated with duloxetine achieved remission. Compared with other treatments, duloxetine had frequently higher rates of nausea, vomiting and dry mouth; however, these differences did not lead to higher discontinuation rates compared with selective serotonin reuptake inhibitors as a class. There is insufficient evidence to draw conclusions about rare but severe adverse events. Current evidence does not warrant the choice of duloxetine over other second-generation antidepressants based on greater efficacy or safety for patients with acute-phase MDD with or without accompanying symptoms such as pain.