Proteins of high molecular weight and low lipophilicity must be administered parenterally to achieve the desired therapeutic blood levels. We investigated the absorption of peptide and protein agents by rat lung following their intratracheal administration, expressing it as percent bioavailability. An aqueous solution and/or a dry powder of calcitonin, insulin, thyrotropin stimulating hormone (TSH), follicle stimulating hormone (FSH), and human chorionic gonadotropin (HCG) was delivered into the exposed trachea of anesthetized rats, and blood was sampled from the jugular vein at specified intervals. The bioavailabilities of TSH, FSH, and HCG delivered in a solution of neutral pH were 2.5, 2.3, and 0.2 %, respectively. Transpulmonary absorption of a solution of these agents, administered with a surfactant or under acidic conditions, was 2-30 times greater than the values obtained in controls. The bioavailabilities of calcitonin, insulin, TSH, FSH, and HCG, given intratracheally as a dry powder, were 11.5, 6.5, 1.6, 0.6, and 0.1%, respectively. Following intratracheal administration, we noted a negative association between molecular weight and bioavailability. The intratracheal route may thus be useful for delivering peptide and protein agents.