OBJECTIVE: To ascertain if antidepressants, as a group, increase the risk for major malformations, as well as assessing each individual antidepressant. METHODS: At The Motherisk Program, we analyzed pregnancy outcomes of women (n = 1243) from prospectively collected cases in our database, who were exposed to antidepressants during their pregnancy. We then compared them with a matched comparison group of women (n = 1243) who were not exposed (nonteratogen group). RESULTS: Women (n = 928) who fit the criteria for inclusion, were exposed in the first trimester of pregnancy, and gave birth to a live-born infant were matched to women (n = 928) in the comparison group. There were 30 (3.2%) major malformations in the antidepressant group and 31 (3.3%) in the comparison group (OR 0.9; 95% CI 0.5 to 1.61). The antidepressants included in the analysis were: bupropion (113), citalopram (184), escitalopram (21), fluvoxamine (52), nefazodone (49), paroxetine (148), mirtazepine (68), fluoxetine (61), trazodone (17), venlafaxine (154), and sertraline (61). CONCLUSIONS: As a group, antidepressant use in the first trimester of pregnancy is not associated with an increased risk for major malformation above the baseline. In addition, no individual antidepressant was associated with an increased risk of a specific malformation.