BACKGROUND. YKL-40 is a growth factor for connective tissue cells and stimulates migration of endothelial cells. Cancer cells, macrophages, and neutrophils secrete YKL-40. Its function in cancer is unknown. High serum YKL-40 levels have been associated with a poor prognosis in patients with several solid tumors. The prognostic impact of serum YKL-40 in metastatic melanoma was evaluated. METHODS. YKL-40 was measured in serial serum samples from 110 patients with metastatic melanoma obtained immediately before and during treatment and from 245 healthy subjects. RESULTS. Patients had higher serum YKL-40 values than healthy subjects (P < 0.001). Pretreatment serum YKL-40 was elevated in 45% of the patients and correlated to site of metastases (P = 0.03) and poor performance status (P = 0.002). Multivariate Cox analysis showed that serum YKL-40 (hazard ratio [HR] = 1.9; 95% confidence interval [CI], 1.2-2.8; P = 0.004) and serum lactate dehydrogenase (LDH) (HR = 1.9; 95% CI, 1.2-2.9; P = 0.004) were independent prognostic factors for survival. A combination variable of elevated serum YKL-40 and LDH quadrupled the risk of early death (HR = 4.4; 95% CI, 2.5-7.7; P < 0.001) compared with patients with normal levels. The combination of YKL-40 and LDH had a stronger prognostic impact than the American Joint Committee on Cancer (AJCC) Stage IV classification. Furthermore, serum samples were available from 12 patients during followup. In 9 of 11 patients a significant increase in serum YKL-40 was observed together with disease progression. In one patient with a lasting complete response, serum YKL-40 remained normal. CONCLUSIONS. An elevated serum YKL-40 was an independent prognostic factor for poor survival in patients with metastatic melanoma. When combining serum YKL-40 and LDH, patients could be separated into three prognostic groups based on the number of elevated biomarkers. The findings should be validated in an independent study.