<p>Abstract</p> <p>Background</p> <p>Members of the genus <it>Nocardia </it>are ubiquitous environmental saprophytes capable to cause human pulmonary, disseminated and cutaneous nocardiosis or bovine mastitis. Innate immunity appears to play an important role in early defense against <it>Nocardia </it>species. To elucidate the contribution of antimicrobial peptides (AMPs) in innate defense against <it>Nocardia</it>, the activity of human α-defensins human neutrophil peptides (HNPs) 1-3, human β-defensin (hBD)-3 and cathelicidin LL-37 as well as bovine β-defensins lingual and tracheal antimicrobial peptides (LAP, TAP) and bovine neutrophil-derived indolicidin against four important <it>Nocardia </it>species was investigated.</p> <p>Results</p> <p>Whereas <it>N. farcinica </it>ATCC 3318 and <it>N. nova </it>ATCC 33726 were found to be susceptible to all investigated human and bovine AMPs, <it>N. asteroides </it>ATCC 19247 was killed exclusively by neutrophil-derived human α-defensins HNP 1-3 and bovine indolicidin. <it>N. brasiliensis </it>ATCC 19296 was found to exhibit complete resistance to investigated human AMPs and to be susceptible only to bovine indolicidin.</p> <p>Conclusion</p> <p>Selected AMPs are capable to contribute to the first line of defense against <it>Nocardia</it>, yet, susceptibility appears to vary across different <it>Nocardia </it>species. Obtained results of neutrophil-derived AMPs to possess the broadest antinocardial spectrum are remarkable, since nocardiosis is characterized by a neutrophil-rich infiltrate <it>in vivo</it>.</p