The objective of this review is to assess the effect of home-based neonatal care provided by community health workers (CHWs) for preventing neonatal, infant and perinatal mortality in resource-limited settings with poor access to health facility-based care. The authors conducted a systematic review, including meta-analysis and meta-regression of controlled trials. The data sources included electronic databases, with a hand search of reviews, abstracts and proceedings of conferences to search for randomized, or cluster randomized, controlled trials evaluating the effect of home-based neonatal care provided by CHWs for preventing neonatal, infant and perinatal mortality. Among the included trials, all from South Asian countries, information on neonatal, infant and perinatal mortality was available in five, one and three trials, respectively. The intervention package comprised three components, namely, home visits during pregnancy (four trials), home-based preventive and/or curative neonatal care (all trials) and community mobilization efforts (four trials). Intervention was associated with a reduced risk of mortality during the neonatal (random effects model relative risk (RR) 0.75; 95% confidence intervals (CIs) 0.61 to 0.92, P = 0.005; I2 = 82.2%, P<0.001 for heterogeneity; high-quality evidence) and perinatal periods (random effects model RR 0.78; 95% CI 0.64 to 0.94, P = 0.009; I2 = 79.6%, P = 0.007 for heterogeneity; high-quality evidence). In one trial, a significant decline in infant mortality (RR 0.85; 95% CI 0.77 to 0.94) was documented. Subgroup and meta-regression analyses suggested a greater effect with a higher baseline neonatal mortality rate. The authors concluded that home-based neonatal care is associated with a reduction in neonatal and perinatal mortality in South Asian settings with high neonatal-mortality rates and poor access to health facility-based care. Adoption of a policy of home-based neonatal care provided by CHWs is justified in such settings.