Background and objective <p>Although cytokeratin-19 fragment CYFRA 21 − 1 is a potential biomarker for idiopathic pulmonary fibrosis (IPF), its relationship to imaging-based structural progression remains unclear. We evaluated whether baseline CYFRA 21 − 1 is associated with fibrotic progression measured via quantitative computed tomography (QCT) and compared these associations with Krebs von den Lungen-6 (KL-6), including longitudinal relationships between changes in serum biomarker levels and QCT measures.</p> Methods <p>We retrospectively analyzed 95 patients with IPF who underwent volumetric chest CT, serum biomarker analysis including CYFRA 21 − 1 and KL-6, and pulmonary function tests at baseline and approximately 1 year. QCT measurements, including fibrosis, ground-glass opacity (GGO)-reticulation extent, and total interstitial lung disease (ILD) extent, were measured using deep learning-based software.</p> Results <p>Baseline CYFRA 21 − 1 was associated with QCT-defined fibrotic progression (odds ratio per 1 ng/mL increase, 1.347; 95% confidence interval [CI], 1.007–1.801). Baseline KL-6 was also associated with fibrotic progression (odds ratio per 100 U/mL increase, 1.085; 95% CI, 1.011–1.164), although the strength of association was lower. Longitudinal increases in CYFRA 21 − 1 were associated with progression of QCT-defined fibrosis (β = 0.943; 95% CI, 0.287–1.600), whereas changes in KL-6 were more closely associated with QCT-derived GGO-reticulation extent (β = 0.429; 95% CI, 0.179–0.680). Neither biomarker was associated with pulmonary function-based progression.</p> Conclusions <p>CYFRA 21 − 1 was associated with QCT-defined fibrotic progression in IPF, whereas KL-6 showed stronger associations with GGO-reticulation extent and total ILD extent on CT. These findings suggest complementary imaging-based association patterns of the two serum biomarkers.</p>