Biomarkers are essential to unravel the locked pathophysiology of any disease. This study investigated the role of biomarkers and their interactions with each other and with the clinical parameters to study the physiology of high-altitude pulmonary edema (HAPE) in HAPE-patients (HAPE-p) against adapted highlanders (HLs) and healthy sojourners, HAPE-controls (HAPE-c). For this, seven circulatory biomarkers, namely, epinephrine, norepinephrine, tyrosine hydroxylase, transforming growth factor beta 1, tumor necrosis factor alpha (TNFα), platelet-derived growth factor beta beta, and C-reactive protein (CRP), were measured in blood plasma of the three study groups. All the subjects were recruited at ~3,500 m, and clinical features such as arterial oxygen saturation (SaO 2), body mass index, and mean arterial pressure were measured. Increased levels of epinephrine, norepinephrine, tyrosine hydroxylase, transforming growth factor-beta 1, and TNFα were observed in HAPE-p against the healthy groups, HAPE-c, and HLs ( P<0.0001). CRP levels were decreased in HAPE-p against HAPE-c and HLs ( P<0.0001). There was no significant difference or very marginal difference in the levels of these biomarkers in HAPE-c and HLs ( P>0.01). Correlation analysis revealed a negative correlation between epinephrine and norepinephrine ( P=4.6E−06) in HAPE-p and positive correlation in HAPE-c ( P=0.004) and HLs ( P=9.78E−07). A positive correlation was observed between TNFα and CRP ( P=0.004) in HAPE-p and a negative correlation in HAPE-c ( P=4.6E−06). SaO 2 correlated negatively with platelet-derived growth factor beta beta (HAPE-p; P=0.05), norepinephrine ( P=0.01), and TNFα ( P=0.005) and positively with CRP (HAPE-c; P=0.02) and norepinephrine (HLs; P=0.04). Body mass index correlated negatively with epinephrine (HAPE-p; P=0.001) and positively with norepinephrine and tyrosine hydroxylase in HAPE-c ( P<0.05). Mean arterial pressure correlated positively with TNFα in HAPE-p and norepinephrine in HLs ( P<0.05). Receiver operating characteristic curve analysis yielded a positive predictive value for these biomarkers with HAPE (area under the curve >0.70, P<0.05). The results clearly suggest that increased plasma levels of these circulatory biomarkers associated with HAPE.