The plasma proteinase inhibitor corresponding to alpha-1-proteinase inhibitor (alpha 1Pl) in humans was isolated from sheep plasma. Ovine alpha 1Pl is of higher molecular weight (62,000 daltons) than is human alpha 1Pl, is resistant to chemical oxidation by N-chlorosuccinimide, and has poor elastase-inactivating power compared with the corresponding inhibitor in humans. However, ovine alpha 1Pl is a potent trypsin inhibitor. Despite the differences indicated above, a partial homology (22 to 35%) exists between human and sheep alpha 1Pl, at least as analyzed through the first 20 residues of the sheep inhibitor. The weak elastase-inhibitory capacity of sheep alpha 1Pl is paralleled by the low content of elastase in the sheep neutrophil granule. These important differences between sheep and human neutrophils and plasma proteinase inhibitors should be borne in mind in designing experiments related to proteolytically mediated lung injury in the former species.