IMPORTANCE Depression during pregnancy and the postpartum period is relatively common and can have adverse effects on both mother and child. OBJECTIVE To systematically review benefits and harms of primary care-relevant interventions to prevent perinatal depression, a major or minor depressive episode during pregnancy or up to 1 year after childbirth, to inform the US Preventive Services Task Force. DATA SOURCES MEDLINE, PubMED (for publisher-supplied records only), PsycINFO, and the Cochrane Central Register of Controlled Trials; surveillance through December 5, 2018. STUDY SELECTION Randomized clinical trials (RCTs) and nonrandomized controlled intervention studies of interventions (eg, behavior-based, antidepressants, dietary supplements) to prevent perinatal depression in general populations of pregnant and postpartum individuals or in those at increased risk of perinatal depression. Large cohort studies were considered for harms of antidepressant use only. DATA EXTRACTION AND SYNTHESIS Two investigators independently reviewed abstracts and full-text articles and quality rated included studies. Random-effects meta-analysis was used to estimate the benefits of the interventions. MAIN OUTCOMES AND MEASURES Depression status; depression symptoms; maternal, infant, and child health outcomes. RESULTS Fifty studies (N = 22 385) that met inclusion criteria were identified. Counseling interventions were the most widely studied interventions. Compared with controls, counseling interventions were associated with a lower likelihood of onset of perinatal depression (pooled risk ratio [RR], 0.61 [95% CI, 0.47-0.78]; 17 RCTs [n = 3094]; I 2 = 39.0%).The absolute difference in the risk of perinatal depression ranged from 1.3% greater reduction in the control group to 31.8% greater reduction in the intervention group. Health system interventions showed a benefit in 3 studies (n = 5321) and had a pooled effect size similar to that of the counseling interventions, but the pooled effect was not statistically significant using a method appropriate for pooling a small number of studies (restricted maximum likelihood RR, 0.58 [95% CI, 0.22-1.53]; n = 4738; I 2 = 66.3%; absolute risk reduction range, −3.1% to −13.1%). None of the behavior-based interventions reported on harms directly. A smaller percentage of participants prescribed sertraline had a depression recurrence compared with those prescribed placebo (7% vs 50%, P = .04) at 20 weeks postpartum in 1 very small RCT (n = 22 analyzed) but with an increased risk of adverse effects to the mother. CONCLUSIONS AND RELEVANCE Counseling interventions can be effective in preventing perinatal depression, although most evidence was limited to women at increased risk for perinatal depression. A variety of other intervention approaches provided some evidence of effectiveness but lacked a robust evidence base and need further research.