Triple I is an important cause of neonatal morbidity and mortality. A relevant clinical question is which type of biological sample [amniotic fluid (AF), maternal blood (MB), cord blood (CB), placenta (PL) and fetal membranes (FM)] reflects the best presence of Triple I. Here, we present a simultaneous, systematic and unbiased study of biological compartments in women with Triple I using a bottom-up proteomics approach. AF, MB, CB, and protein lysates of FM and PL from 4 women with Triple I (GA: 28±1 wks) and 5 women (GA: 31±1 wks, p=.07) with idiopathic PTB (CRL). All biological samples were albumin depleted, tryptic digested and subjected to state-of-art mass spectrometry by using a Velos Pro mass spectrometer coupled to a PepMap Easy-Spray C18 column on a 1D nano Acquity UPLC. Spectra were searched through Proteome Discoverer 1.4 with SEQUEST against Uniprot human database. Protein network analysis was done utilizing Cytoscape software platform (V.3.7.1) with STRING and DyNet Analyzer. With a cutoff of 2 for peptide spectra matching, 1,126 proteins were identified in at least one compartment. The proteins were gene enriched to 708 nodes and 4,904 edges (confidence level 0.90) for all the compartments of Triple I patients (Fig A). The AF had the top dynamic Protein-Protein-Interaction network confirming AF harbors most biomarkers discriminative of Triple I. FM demonstrated the second most varied network after AF, while other compartments remained less perturbed. In the AF the most varying genes clusters related to antibacterial and immune pathways. Among them, histones and keratins constituted two distinctive networks with least heterogeneity. Compared with CRL patients the keratin cluster from Triple I patients displayed a shift between inflammation barrier to tissue repair (Fig B). Our novel analysis suggests that AF is the most relevant biological sample to identify Triple I. In Triple I there is a shift between fetal inflammation to tissue repair, which cannot entirely be identified through the analysis of FM, MB, CB or PL.