INTRODUCTION Evidence for the effectiveness of drug treatment for depression in primary care settings remains limited, with little information on newer antidepressant classes. AIM To update an earlier Cochrane review on the effectiveness of antidepressants in primary care to include newer antidepressant classes, and to examine the efficacy of individual agents. METHODS Selection criteria included antidepressant studies with a randomly assigned placebo group where half or more subjects were recruited from primary care. The Cochrane Collaboration Depression, Anxiety and Neurosis (CCDAN) group searched multiple databases to identify eligible studies. Data extraction was performed independently by two reviewers. Data were analysed using Revman version 5.3.5. RESULTS In total, 17 papers and 22 comparisons were included for analysis. Significant benefits in terms of response were found for tricyclic antidepressants (TCA) with a relative risk (RR) = 1.23 (95% CI, 1.01-1.48), and serotonin selective reuptake inhibitors (SSRI) with a RR = 1.33 (95% CI, 1.20-1.48). Mianserin was effective for continuous outcomes. Numbers needed to treat (NNT) for TCA = 8.5; SSRI = 6.5; and venlafaxine = 6. Most studies were industry-funded and of a brief duration (≤ 8 weeks). There was evidence of publication bias. There were no studies comparing newer antidepressants against placebo. CONCLUSION Antidepressants such as TCA, SSRI, SNRI (serotonin-norepinephrine reuptake inhibitor) and NaSSA (noradrenergic and specific serotonergic antidepressant) classes appear to be effective in primary care when compared with placebo. However, in view of the potential for publication bias and that only four studies were not funded by industry, caution is needed when considering their use in primary care.