YKL-40, a growth factor for connective tissue cells, is secreted by cancer cells and macrophages. Elevated serum YKL-40 in patients with metastatic carcinoma has been associated with poor prognosis. We evaluated serum YKL-40 in 131 patients with small cell lung cancer (SCLC). Twenty-two percent of the patients with limited disease and 40% of the patients with extensive disease had elevated serum YKL-40. The median survival was 5.1 months for patients with elevated serum YKL-40 and 9.0 months for patients with normal serum YKL-40. Patients with elevated serum YKL-40 had increased hazard for death within the first 6 months after the start of chemotherapy compared to patients with normal serum YKL-40 (HR = 2.06, P = 0.009). Multivariate Cox analysis including routine prognostic variables showed that serum YKL-40 (P = 0.02) is independent of prognostic variables for survival within the first 6 months. Studies are needed to determine the function of YKL-40 in SCLC.