Previous narrative reviews in this area have concluded that there are few interventions that are likely to be beneficial and that further high-quality research is required. Our objective was to perform a review of systematic reviews of the effectiveness of interventions for the prevention of small-for-gestational age (SGA) fetuses and perinatal mortality, to summarize the most up-to-date evidence and assess quality. Searches were carried out by using Medline, Embase, Cochrane Library and DARE (inception to September 2011), by hand searching of journal and reference lists and by contact with experts. Systematic reviews of randomized controlled trials were selected. Two reviewers independently selected articles and assessed the methodological and reporting quality. Data were extracted on study characteristics, quality and results. Summary data were presented as relative risks (RRs) and 95% confidence intervals (CIs). There were 834 randomized controlled trials (>668 672 participants), reporting on 45 different interventions. The most effective interventions to prevent the SGA fetus were antiplatelets at <16 weeks in women at risk of pre-eclampsia (RR 0.47; CI 0.30–0.74) and progesterone therapy for prevention of preterm birth (RR 0.64; CI 0.49–0.83). For the prevention of perinatal mortality in high-risk women, antiplatelets (RR 0.69; CI 0.53–0.90) and antenatal corticosteroids (RR 0.77; CI 0.67–0.89) were effective interventions. It is concluded that effective interventions are available for reducing the occurrence of SGA fetuses and preventing related perinatal mortality. Some are effective in all women, while others target specific co-morbidities. There is a need to consider a comprehensive approach to primary prevention that targets SGA along with pre-eclampsia and preterm birth.