Staphylococcus aureus (S. aureus) is a prevalent opportunistic pathogen that can cause superficial infections as well as a range of severe diseases, possibly leading to death. Around 30 % of the population is colonized by S. aureus, preferably in the anterior nares. Overuse of antibiotics in healthcare and livestock accelerates the development of resistances in bacteria, which can lead to the emergence of multidrug-resistant species, such as methicillin-resistant S. aureus (MRSA). An alternative, promising control strategy is based on microbiome-mediated colonization resistance. Colonization resistance may occur via various mechanisms of complex microbial interactions, including the production of antimicrobials, referred to as bacteriocins. Staphylococcus epidermidis (S. epidermidis) is an important member of the nasal microbiota due to its production of diverse bacteriocins, which is associated with a high capacity for colonization resistance, especially against S. aureus. Nasal S. epidermidis strain IVK83 produces a highly potent bacteriocin, called epifadin, which effectively inhibits S. aureus. However, the phenotypic response to epifadin varies among Staphylococci, and our understanding of how resistance is mediated remains limited. We aimed to identify genetic features of Staphylococci that confer resistance to epifadin. We investigated the ABC transporters EfiF and EfiG, encoded in the biosynthetic gene cluster of epifadin, as potential resistance factors. To this end, we performed spot assays on susceptible S. aureus strains provided with a heterologous expression of the respective transporters, which did not change epifadin susceptibility in S. aureus. However, we demonstrated that S. epidermidis IVK83, deficient in both efiFG expression, shows decreased antimicrobial activity on S. aureus suggesting an impaired secretion of the bacteriocin. Independently, transposon mutagenesis of the epifadin-resistant S. epidermidis 1457 revealed an epifadin-susceptible clone, disrupted in the expression of a putative ABC transporter, referred to as ergB. We therefore propose that the erg-encoded transport system contributes to epifadin resistance in Staphylococci.