Histological chorioamnionitis (HCA) is an intrauterine inflammatory condition increasing the risk for preterm birth, death, and disability due to persistent systemic and localized inflammation. The immunologic mechanisms sustaining this response in the preterm newborn remain unclear. We sought to determine the consequences of HCA exposure on the fetal CD4+ T lymphocyte exo-metabolome. We cultured naïve CD4+ T lymphocytes from HCA-positive and HCA-negative preterm infants matched for gestational age, sex, race, prenatal steroid exposure, and delivery mode. We collected conditioned media samples before and after a 6 hour in vitro activation of naïve CD4+ T lymphocytes with soluble Staphylococcal enterotoxin B (SEB) and anti-CD28. We analyzed samples by ultra performance liquid chromatography ion mobility-mass spectrometry (UPLC-IM-MS). We determined the impact of HCA on the CD4+ T lymphocyte exo-metabolome and identified potential biomarker metabolites by multivariate statistical analyses. We discovered that: (1) CD4+ T lymphocytes exposed to HCA exhibit divergent exo-metabolomic profiles in both naïve and activated states; (2) ~30% of detected metabolites differentially expressed in response to activation were unique to HCA-positive CD4+ T lymphocytes; and (3) metabolic pathways associated with glutathione detoxification and tryptophan degradation were altered in HCA-positive CD4+ T lymphocytes; and (4) flow cytometry and cytokine analyses suggested a bias towards a TH1-biased immune response in HCA-positive samples. HCA exposure primes the neonatal adaptive immune processes by inducing changes to the exo-metabolomic profiles of fetal CD4+ T lymphocytes. These exo-metabolomic changes may link HCA exposure to TH1 polarization of the neonatal adaptive immune response.