Serum YKL-40 levels have been associated with a poor prognosis in patients with several cancer types. However, the role of YKL-40 and its relationship with colorectal cancer are poorly understood. Pretreatment serum levels of YKL-40 were determined in 86 patients with colorectal cancer and from 20 healthy controls. The serum YKL-40 levels in colorectal cancer patients were compared with those in healthy controls, and we retrospectively assessed the association between serum YKL-40 levels and clinicopathological findings and progression-free survival. Colorectal patients had a median serum YKL-40 level of 216 ng/mL (range 22.3-1, 253.2 ng/mL). Expression of serum YKL-40 levels was significantly higher in colorectal cancer patients compared with healthy controls, and the median serum values were 216 and 62.5 ng/mL, respectively (p < 0.01). No correlation was observed between progression-free survival and the type of chemotherapy regimen used tumor stage, sex, or histologic types. Patients with high serum YKL-40 levels [greater than the median level for all patients (216 ng/mL)] had a significantly shorter survival than patients with serum YKL-40 levels below the median (median progression-free survival, 36 vs. 50 months; p = 0.003). In multivariate analysis, the serum YKL-40 level, and the presence of distant metastasis were independent, statistically significant prognostic factors. The pretreatment serum YKL-40 level was identified as a new, independent prognostic biomarker in patients with colorectal cancer and may help to determine the individual prognosis of these patients.