The metabolome of World Trade Center (WTC) particulate matter (PM) exposure has yet to be fully defined and may yield information that will further define bioactive pathways relevant to lung injury. A subset of Fire Department of New York firefighters demonstrated resistance to subsequent loss of lung function. We intend to characterize the metabolome of never smoking WTC-exposed firefighters, stratified by resistance to WTC-Lung Injury (WTC-LI) to determine metabolite pathways significant in subjects resistant to the loss of lung function. The global serum metabolome was determined in those resistant to WTC-LI and controls (n = 15 in each). Metabolites most important to class separation (top 5% by Random Forest (RF) of 594 qualified metabolites) included elevated amino acid and long-chain fatty acid metabolites, and reduced hexose monophosphate shunt metabolites in the resistant cohort. RF using the refined metabolic profile was able to classify cases and controls with an estimated success rate of 93.3%, and performed similarly upon cross-validation. Agglomerative hierarchical clustering identified potential influential pathways of resistance to the development of WTC-LI. These pathways represent potential therapeutic targets and warrant further research.