Preterm birth (PTB) is the leading cause of infant mortality and morbidity worldwide. Both preterm labor and neonatal injuries have been linked to inflammation. Of all mediators of inflammation, the major pro-inflammatory cytokine IL-1ß has been shown to trigger a specific pattern of gene expression in uterus and placenta resulting in PTB and in neonatal organ injury and significant fetal demise. Here, we show that a small peptide noncompetitive IL-1R antagonist (rytvela, labeled 101.10) designed and characterized by us, exerts potential therapeutic efficacy in preventing PTB and improving neonatal outcome. Effects of 101.10 were compared to a clinically available IL-1R competitive antagonist (Kineret). Our results show that 101.10 selectively inhibits the downstream stress-associated factors JNK, p38 and c-jun and the small GTPase Rho in myometrial smooth muscle cells and uterine explants and desirably does not interfere with the transcription factor NF-kB activity. Administration of 101.10 to pregnant mice revealed efficacy in preventing IL-1ß-, LTA- and LPS-induced PTB by down-regulating a series of proinflammatory mediators in uterus, placenta, fetal membranes, maternal circulating white blood cells and amniotic fluids. In pregnant mice treated with IL-1ß, 101.10 increased neonatal survival, and this was associated later in life with improved tissue (lung, intestine and brain) analyzed by histology. Specifically, 101.10 protected against IL-1ß-induced cerebral microvascular degeneration, loss in brain mass, which resulted in improved amplitude and latency of visual evoked potential, suggesting normalized brain function reflected in preservation of synaptic transmission through the brain of pups. In LPS-induced PTB (which mimic a gram – infection during pregnancy), 101.10 also increased neonatal survival in addition to decreasing the expression of proinflammatory mRNA transcripts in brain. 101.10 conveyed superior or comparable efficacy to Kineret in all assays performed; Kineret was largely ineffective at prolonging preterm gestation or improving neonatal outcomes, as already reported by other groups. In summary, our data describe a new potential therapeutic candidate that selectively modulates IL-1R-related signaling (thereby preserving NF-?B activity) which is effective in preventing the onset of PTB and associated adverse neonatal outcomes.