Pulmonary vascular loss is an early feature of chronic obstructive pulmonary disease. Biomarkers of inflammation and of metabolic syndrome predict loss of lung function in World Trade Center (WTC) lung injury (LI). We investigated if other cardiovascular disease (CVD) biomarkers also predicted WTC-LI. This nested case-cohort study used 801 never-smoker, WTC-exposed firefighters with normal pre-9/11 lung function presenting for subspecialty pulmonary evaluation (SPE) before March 2008. A representative subcohort of 124 out of 801 subjects with serum drawn within 6 months of 9/11 defined CVD biomarker distribution. Post-9/11 forced expiratory volume in 1 s (FEV1) at defined cases were as follows: susceptible WTC-LI cases with FEV1 ≤77% predicted (66 out of 801) and resistant WTC-LI cases with FEV1 ≥107% predicted (68 out of 801). All models were adjusted for WTC exposure intensity, body mass index at SPE, age on 9/11 and pre-9/11 FEV1. Susceptible WTC-LI cases had higher levels of apolipoprotein-AII, C-reactive protein and macrophage inflammatory protein-4 with significant relative risks (RRs) of 3.85, 3.93 and 0.26, respectively, with an area under the curve (AUC) of 0.858. Resistant WTC-LI cases had significantly higher soluble vascular cell adhesion molecule and lower myeloperoxidase, with RRs of 2.24 and 2.89, respectively (AUC 0.830). Biomarkers of CVD in serum 6 months post-9/11 predicted either susceptibility or resistance to WTC-LI. These biomarkers may define pathways either producing or protecting subjects from pulmonary vascular disease and associated loss of lung function after an irritant exposure.