1. Metabolism of [14C]nicotine has been studied in the isolated perfused dog lung. [14C]Nicotine, 50 mug every 30 s for 10 min administered via the pulmonary artery, undergoes first pass metabolism to a small extent. [14C]Cotinine was detected in the venous blood. Of the injected activity, 6 percent was in the lung at the end of experiment; 60 percent being present as [14C]nicotine and 20 percent as [14C]nicotine-1'-oxide. 2. When [14C]nicotine was administered in cigarette smoke a greater degree of metabolism was observed at first pass. Pyrolysis products of [14C]nicotine also were present in the venous blood. Lungs after smoke exposure contained 30 percent of administered radioactivity, with a substantial proportion of [14C]nicotine-1'-oxide. 3. Administration of [14C]nicotine-labelled smoke to lung preparations, on closed circuit, gave significant amounts of [14C]cotinine and other metabolites over a 2 h period. Lung tissue contained approx. 40 percent of injected dose, of which 25 percent only was [14C]nicotine. Large proportions of [14C]cotinine and [14C]nicotine-1'-oxide were present but 45 percent of the activity was present as other unidentified pyrolysis products. [14C]Demethyl cotinine was detected.