Objectives: YKL-40 is an acute phase protein elevated in patients with infectious and inflammatory diseases. We tested the hypothesis that baseline elevated YKL-40 is associated with increased risk of future infectious disease in healthy individuals in the general population. Methods: We prospectively followed 94 665 individuals from the Danish general population for up to 23 years and analysed for plasma YKL-40 levels (n = 21 584) and CHI3L1 rs4950928 genotype (n = 94 184). Endpoints were any infection, bacterial pneumonia, urinary tract infection, skin infection, sepsis, diarrhoeal disease, and other infections. Results: For YKL-40 percentile category 91–100% versus 0–33%, the multifactorially and C-reactive protein (CRP) adjusted hazard ratios were 1.71 (95% confidence interval 1.50–1.96; p 4 × 10⁻¹⁴) for any infection, 1.97 (1.64–2.37; p 4 × 10⁻¹³) for bacterial pneumonia, 1.62 (1.24–2.11; p 0.002) for urinary tract infection, 1.74 (1.31–2.32; p 2 × 10⁻⁴) for skin infection, 1.76 (1.25–2.46; p 0.004) for sepsis, 1.90 (1.29–2.78; p 0.002) for diarrhoeal disease and 2.71 (1.38–5.35; p 0.01) for other infections. In multifactorially and CRP-adjusted models, a twofold increase in YKL-40 was associated with increased risk of all infectious disease endpoints. Mendelian randomization did not support causality, as CHI3L1 rs4950928 was associated with 94% and 190% higher YKL-40 levels (for CG and CC versus GG genotype), but not with increased risk of any infectious disease endpoint. Discussion: Baseline elevated plasma YKL-40 was not a cause but a strong marker of increased risk of future infectious diseases in individuals in the general population.