Preterm delivery (PTD) can effect up to 13% of pregnancies in developed countries with as many as half of these caused by infection-driven inflammation. Engagement of the bacterial component lipopolysaccharide (LPS) with toll-like receptor 4 (TLR4) is a well-established trigger of PTD and poor neonatal outcomes in experimental mouse models. We aimed to investigate whether (+)-naloxone, a small molecule TLR4 antagonist, can prevent the deleterious effects of LPS on pregnancy in a mouse model. Pregnant mice were challenged with either LPS (i.p.) or heat-killed E. coli (in utero) in late gestation, both of which induced PTD and fetal loss. Co-administration of (+)-naloxone (the non-opioid isomer of naloxone) acted to reverse the effects of LPS and E. coli. Gene expression analysis revealed that mice given E. coli had a surge in pro-inflammatory cytokines, including Il1a, Il1b, Il6 and Tnf in the uterus, decidua, placenta and fetal membrane, while treatment of infected mice with (+)-naloxone curbed cytokine expression. To examine the effect of LPS and (+)-naloxone on the health of surviving progeny, pups were weighed fortnightly until 20 weeks of age, with body composition determined by dual energy x-ray absorbtiometry (DEXA) scans at 8, 14 and 20 weeks of age and a 20 week autopsy. Female offspring were largely unaffected, however male offspring exposed to LPS in utero had less muscle mass and more fat mass, as measured by DEXA and autopsy, compared to offspring exposed to vehicle. Administration of (+)-naloxone corrected the LPS induced body composition change in the male progeny. Collectively these data demonstrate that TLR4 ligation by infectious agents plays an important role in initiating the pro-inflammatory response which leads to PTD and fetal loss, and that (+)-naloxone is worthy of consideration as a candidate therapeutic agent for women at risk of PTD.