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We hypothesized that metabolite quantification across the pulmonary vascular bed in connective tissue disease\u2013associated (CTD-associated) PAH would identify transpulmonary gradients of pathobiologically relevant metabolites, in an exercise stage\u2013specific manner. Sixty-three CTD patients with established or suspected PAH underwent exercise right heart catheterization. Using mass spectrometry\u2013based metabolomics, metabolites were quantified in plasma samples simultaneously collected from the pulmonary and radial arteries at baseline and during resistance-free wheeling, peak exercise, and recovery. We identified uptake and excretion of metabolites across the pulmonary vascular bed, unique and distinct from single vascular site analysis. We demonstrated the physiological relevance of metabolites previously shown to promote disease in animal models and end-stage human lung tissues, including acylcarnitines, glycolytic intermediates, and tryptophan catabolites. 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