The toxicity and marginal effectiveness of cytotoxic chemotherapy in metastatic non-small cell lung cancer (NSCLC) necessitates the search for new agents. Preliminary data in lung cancer and other malignant and premalignant disorders have identified retinoid compounds as potentially useful antitumor agents. Twenty-eight patients with metastatic NSCLC were treated with oral all-trans retinoic acid in a phase II trial. The study population consisted of patients with excellent performance status and minimal weight loss. Toxicities were generally mild and included cutaneous effects, headache, and myalgia. A significant number of patients developed elevations of hepatic transaminases or hyperlipidemia and 3 patients had treatment-related leukocytosis. Two patients (8%) achieved a partial response, and 1 had a mixed response. The duration of remission in the 2 responders was 7 and 13 months and the median survival of all patients 7 months. Therefore, all-trans retinoic acid has minimal activity as a single agent in NSCLC but warrants further study in combination with biological agents and chemotherapy.