The capacity of pretherapeutically assessed neuron-specific enolase (NSE) to differentiate between small cell lung cancer (SCLC) and mediastinal tumors was investigated retrospectively in a series of 320 patients. NSE was found to be increased in 95/130 (73.1%) patients with SCLC, in 4/62 (6.5%) patients with Hodgkin's disease, in 10/58 (17.2%) patients with non-Hodgkin's lymphoma, in 5/16 (31.3%) patients with teratoma, and in 6/54 (11.1%) patients with thymoma. The cut-off value, defined as the 95% percentile of a reference population suffering from benign pulmonary disorders (n = 192), was set at 13.8 ng/ml. When this discrimination level was increased to 26.4 ng/ml, which corresponds to a 95% specificity versus the total group with mediastinal tumors, SCLC was recognized with a detection rate of only 49.2%. In conclusion, increased NSE concentrations in a patient with a hilar mass and/or mediastinal widening on X-ray are not always diagnostic of SCLC due to the high rate of elevated NSE values associated with mediastinal tumors. However, in a patient who presents with a hilar mass and a high NSE level, bronchoscopy is always indicated to obtain adequate specimens for histology in order to plan an appropriate therapeutic regimen.