Background: Accumulating evidence suggests that prenatal depression is associated with altered birthweight in the offspring. The hormone prolactin (PRL) plays an important role in the etiology of mood disorders in women, especially for depression. We tested the hypotheses that maternal prenatal PRL levels can significantly influence neonatal birthweight and adequate PRL levels can alleviate prenatal depression-induced normal neonatal birthweight loss risk. Methods: The study population consisted of 392 mother-infant dyads. Symptoms of maternal prenatal depression were evaluated through the Edinburgh Postnatal Depression Scale and concentrations of plasma PRL and placental growth hormone (PGH) were measured before the delivery and umbilical cord plasma levels of insulin-like growth factor -1(IGF1) were measured at birth. The associations among maternal depressed symptoms, concentrations of related hormones and infant's birthweight were examined through linear regressions models. Results: Infants of low maternal PRL had a 0.169 unit (95%CI, -0.488,- 0.130) decrease in the birthweight Z-score compared to infants whose mothers had adequate PRL. Infants of depressed mothers with low PRL had a 0.253 unit(95%CI, -0.853,-0.369) decrease in the birthweight Z score compared to infants whose mothers had adequate PRL and normal emotion. Among infants of depressed mothers, we demonstrated that neonatal birthweight was reduced by a 0.285 unit if the mothers had low PRL concentrations compared to adequate PRL concentrations. As compared with low maternal PRL concentrations, high PRL concentrations were associated with an increase in the concentrations of IGF1 in offspring, but no association with PGH.Conclusion: We found that prenatal depression and low maternal PRL levels are at increased risk of normal infant’ s birthweight loss as measured by weight Z-score and sufficient maternal PRL levels would mitigate the adverse impact of prenatal depression on birthweight. We also found that prenatal depression and low PRL concentrations were associated with reduced fetal IGF1.