Serum concentrations of neuron-specific enolase (NSE) were measured in 135 patients with benign pulmonary diseases who also underwent a clinical, laboratory, and radiologic evaluation. Eleven percent of the patients as a whole and 27.3% of those who were tuberculous had abnormal serum levels of NSE. Significant differences in NSE levels were observed among the six diagnostic groups evaluated (p = 0.002). Males had higher levels than females (p = 0.003), and patients infected with the human immunodeficiency virus (HIV) had higher NSE levels than those not infected (p = 0.0026). Patients with alveolar infiltrates or an interstitial pattern on chest X-ray had higher NSE levels than those with normal radiographs (p = 0.003 and p = 0.01, respectively). In fact, only 3.6% of the patients with normal radiographs had above-normal levels of NSE. Direct damage to the neural or neuroendocrine lung cells or some degree of local hypoxia is likely to play a role in the increase in NSE in these patients. The small number and degree of abnormal values of NSE observed in this study make it unlikely that an underlying benign lung disease will substantially modify the interpretation of an increased NSE value in patients with lung cancer. However, care should be taken in interpreting a moderately abnormal NSE value in the cancer patient in the presence of lung infiltrates such as obstructive pneumonitis.