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Background/objectives: Increased systemic concentrations of YKL-40 are seen in various inflammatory conditions. We explored the relationship between the serum YKL-40 concentrations and subsequent disease severity in patients with acute pancreatitis (AP)., Methods: Consecutive adults with AP were prospectively enrolled, and classified as having mild, moderate or severe disease. On admission and 48 h later, C-reactive protein (CRP), YKL-40, interleukin-6 and 8 (IL-6, IL-8), and tumor necrosis factor alpha (TNF-α) concentrations were measured. Patients were also classified as those with low (<50 ng/mL, in the range seen in 30 age and sex-matched non-AP subjects), high (≥190 ng/mL, seen in most of the other inflammatory conditions), and intermediate YKL-40 (50-189 ng/mL)., Results: Incidence of mild, moderate and severe AP among the 150 enrolled patients was 80 (53.3 %), 59 (39.3 %), and 11 (7.4 %), respectively. Both on admission and 48 h later, high YKL-40 (vs. intermediate or low) was strongly associated with higher odds of a more severe AP, independently of the concurrent IL-8 and TNF-α concentrations (OR around 3.5-4.0, or higher). On admission, the association was independent also of the concurrent CRP, whereas the association between the later concentrations and the outcome was conditional on CRP - uncertain at low, strong at high CRP. The high YKL-40 - outcome association at both time-points was conditional on concurrent IL-6: uncertain if IL-6 was low, strong if IL-6 was high., Conclusions: Serum YKL-40 is a plausible candidate for further evaluation as an early biochemical indicator of subsequent AP severity, particularly if considered jointly with CRP and/or IL-6., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 IAP and EPC. Published by Elsevier B.V. All rights reserved.)