The nonciliated bronchiolar epithelial (or Clara) cell is considered the primary pulmonary site of cytochrome P-450-dependent monooxygenase activity. Despite the general conception that Clara cells are restricted to bronchioles, we have previously shown that a nonciliated cell with the cytological features of the Clara cell predominates throughout rabbit tracheobronchial airways. The present study was designed to determine if the cytochrome P-450 monooxygenase system has the same distribution. Trachea, terminal bronchioles and 3 generations of bronchi were selected by microdissection from fixed lungs of adult specific-pathogen-free rabbits. Serial sections of paraffin-embedded tissue were stained with either Alcian blue/periodic acid Schiff's (AB/PAS) or with antisera to one of the following: cytochrome P-450 form 2, form 5, or NADPH-dependent cytochrome P-450 reductase. The majority of nonciliated epithelial cells lining all 5 airway generations were PAS+ and AB-. Nonciliated cells in all 5 airway generations reacted positively with all three antisera. The primary deposition site was the apical portion of nonciliated cells. Other sites included ciliated surfaces and vascular endothelium. Reaction products from all three antisera had the same localization pattern. We conclude that (1) the cytochrome P-450 monooxygenase system is distributed throughout the tracheobronchial airways of the rabbit and (2) the Clara cells of the trachea and bronchi are functionally, as well as structurally, similar to those of the bronchioles.