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Introduction Idiopathic pulmonary fibrosis (IPF) is a disease of high morbidity and mortality. We previously identified a novel subset of pathological fibroblasts, characterised by CTHRC1 expression, uniquely present in fibrotic lung diseases. The aim of this study was to determine the association of serum CTHRC1 with clinical outcomes in IPF to assess its potential as a biologically relevant biomarker.Methods A retrospective longitudinal cohort study was performed using two cohorts including a discovery cohort of 352 patients with IPF from the University of California San Francisco (UCSF) and a validation cohort of 1156 patients with IPF from the Pulmonary Fibrosis Foundation (PFF) as well as 41 healthy controls. Serum CTHRC1 was measured by ELISA and patients were stratified by quartiles of CTHRC1 for analysis. For a subset of patients, serial serum and lung CTHRC1 expression was measured. Associations between CTHRC1 and clinical outcomes, including baseline lung function, lung function trajectory and transplant-free survival were assessed.Results Serum CTHRC1 was elevated in patients with IPF compared with healthy controls (UCSF 31 661±11 651 and PFF 33 916±14 547 vs 24 409±8630 pg/mL, p<0.001). Elevated circulating CTRHC1 was associated with lower forced vital capacity (FVC) per cent predicted and diffusing capacity of carbon monoxide per cent predicted at baseline and a greater decline in FVC over 1 year. In both cohorts, higher CTHRC1 level was associated with worse transplant-free survival (p<0.03).Discussion Circulating CTHRC1 levels are elevated in patients with IPF and associated with disease severity and overall survival. These findings further support the biological significance of CTHRC1 in IPF as a pathological marker and potential biomarker reflecting the burden of pathological fibroblasts in IPF.