The prognostic value of serum neuron-specific enolase (NSE) and lactate dehydrogenase (LDH) was prospectively assessed in 42 patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) treated within two chemotherapy trials. Pretreatment NSE levels ranged from 4.6 to 34.6 ng/mL (median value, 7.5) and were above 10 ng/mL in ten patients (23.8%). LDH levels varied between 85 U/L and 2,484 U/L (median value, 220) and were above 250 U/L in 12 patients (29.3%). Elevated levels of both enzymes were significantly more common in patients with metastatic disease than in those with locoregional disease (40% v 9% for NSE and 40% v 18% for LDH, respectively). Strong positive correlation (correlation factor 0.693) was found between NSE and LDH serum levels. The levels of both markers did not correlate with age, sex, previous therapy, performance status, or histology. Responses to chemotherapy were seen more frequently in patients with elevated NSE levels (six of ten, 60%) than in those with normal values (seven of 32, 22%; P = .02). Similar correlation was found for LDH: Response was seen in seven of 12 patients with elevated levels (58%) and in six of 29 (21%) of those with normal values (P = .02). In a logistic regression analysis, both markers considered individually remained significant when adjusted by sex, age, performance status, prior therapy, histology, and extent of disease. Three pretreatment characteristics, high levels of NSE and LDH (both considered as continuous variables) and metastatic disease, were found to be associated with shorter survival; with adjustment for extent of disease, however, NSE and LDH were no longer correlated with shorter survival. These data suggest potential clinical value of NSE and LDH determination in treatment selection of NSCLC patients.