Cellular communication network 2 (CCN2) is a secreted matricellular protein associated with pulmonary arterial hypertension (PAH) but has not been studied relative to PAH severity, outcomes, or right ventricle (RV) structure and function in a large human cohort and preclinical animal model. This study assessed the associations between CCN2 and PAH severity, survival, hemodynamic measurements, and cardiovascular dysfunction. Serum CCN2 levels were compared in 2548 adults with PAH and 216 controls. CCN2 levels in PAH patients were compared to functional and hemodynamic measurements, and survival outcomes. RV-pulmonary artery coupling and RV morphology were also assessed in a small subset of patients via pressure-volume loops and cardiac magnetic resonance imaging. In a preclinical PAH model, plasma CCN2 levels were compared between ventricles with PAH progression. CCN2 mRNA levels in both ventricles in the preclinical model were measured to compare with morphologic histologic variables. CCN2 serum levels were significantly higher in PAH compared to controls (