Lonidamine (LND) interferes with the energy mechanisms of neoplastic cells and decreases the oxygen consumption in human and experimental tumors. The present study was performed in advanced non-small cell lung cancer patients, previously untreated, to confirm the preliminary data of activity against this kind of tumor. LND was given orally in three divided doses increasing to 250 mg/m2 over 4 days. Thirty-six patients were evaluable for toxicity and 33 for response. Partial responses were 3 (9%) and stabilization of disease 15 (45,5%). Recorded side effects (testicular pain, nausea and vomiting, skin hyperesthesia) were mostly mild to moderate with the exclusion of myalgias. Chronic treatment was devoid of haematological, renal, cardiac and pulmonary toxicities. LND as single agent seems to be marginally active in advanced non-small cell lung cancer.