Synthetic leukotriene C4 (LTC4) and leukotriene D4 (LTD4) were examined on isolated human tracheal and bronchial smooth muscle. Both LTC4 and LTD4 produced slowly developing contraction of trachealis and bronchus which were submaximal (70–85% of the carbachol maximum) and were not blocked by 1.0 μM atropine, 5.0 μM mepyrarnine, or 5.6 μM indomethacin. The EC50's for LTC4 and LTD4 were 10.3 and 1.8 nM on trachealis and 1.8 and 1.7 nM on bronchus, respectively. LTD4 was in excess of 20 000 times more potent than acetylcholine on some bronchial and tracheal tissues. Similar differences in potency were obtained in some tissues when LTC4 and LTD4 were compared with histamine. Tissues pretreated for 30 min with 2.0–4.0 μM FPL-55712 were less reactive to LTC4 and LTD4 than untreated control tissues. Established contractions to LTC4 and LTD4 persisted despite washing with fresh Krebs solution, were partially reversed by FPL-55712 (0.5–10 μM) and the Ca2+ channel blocker D-600 (5–10 μM), but were completely reversed by the catecholamine adrenaline (1.0 μM) and by high concentrations of FPL-55712 (>20 μM). The marked potency of the leukotrienes on human tracheal and bronchial smooth muscle suggests an important role for these lipoxygenase products in respiratory disease.