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-a) 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 e189 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-a concentrations (OR around 3.5e4.0, 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 e uncertain at low, strong at high CRP. The high YKL-40 e 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.