AbstractPostural orthostatic tachycardia syndrome (POTS) is a cardiovascular autonomic disorder characterized by excessive heart rate increase on standing, leading to debilitating symptoms with limited therapeutic possibilities. Proteomics is a large-scale study of proteins that enables a systematic unbiased view on disease and health, allowing stratification of patients based on their protein background. The aim of the present study was to determine plasma protein biomarkers of POTS and to reveal proteomic pathways differentially regulated in POTS. We performed an age- and sex-matched, case–control study in 130 individuals (case–control ratio 1:1) including POTS and healthy controls. Mean age in POTS was 30 ± 9.8 years (84.6% women) versus controls 31 ± 9.8 years (80.0% women). We analyzed plasma proteins using data-independent acquisition (DIA) mass spectrometry. Pathway analysis of significantly differently expressed proteins was executed using a cutoff log2 fold change set to 1.2 and false discovery rate (p-value) of < 0.05. A total of 393 differential plasma proteins were identified. Label-free quantification of DIA-data identified 30 differentially expressed proteins in POTS compared with healthy controls. Pathway analysis identified the strongest network interactions particularly for proteins involved in thrombogenicity and enhanced platelet activity, but also inflammation, cardiac contractility and hypertrophy, and increased adrenergic activity. Our observations generated by the first use a label-free unbiased quantification reveal the proteomic footprint of POTS in terms of a hypercoagulable state, proinflammatory state, enhanced cardiac contractility and hypertrophy, skeletal muscle expression, and adrenergic activity. These findings support the hypothesis that POTS may be an autoimmune, inflammatory and hyperadrenergic disorder.