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Abstract Clostridioides (Clostridium) difficile causes severe diarrheal disease that is directly associated with antibiotic use and resistance. Although C. difficile demonstrates intrinsic resistance to many antimicrobials, few genetic mechanisms of resistance have been characterized in this pathogen. In this study, we investigated the putative resistance factor, CD1240 (VanZ1), an ortholog of the teicoplanin resistance factor, VanZ, of Enterococcus faecium. In C. difficile, the vanZ1 gene is located within the skin element of the sporulation factor σK, which is excised from the mother cell compartment during sporulation. This unique localization enabled us to create a vanZ1 deletion mutant by inducing excision of the skin element. The Δ skin mutant exhibited moderately decreased resistance to teicoplanin and had small effects on growth in some other cell-surface antimicrobials tested. Examination of vanZ1 expression revealed induction of vanZ1 transcription by the antimicrobial peptide LL-37; however, LL-37 resistance was not impacted by VanZ1, and none of the other tested antimicrobials induced vanZ1 expression. Further, expression of vanZ1 via an inducible promoter in the Δ skin mutant restored growth in teicoplanin. These results demonstrate that like the E. faecium VanZ, C. difficile VanZ1 contributes to low-level teicoplanin resistance through an undefined mechanism. Highlights • C. difficile encodes a conserved ortholog of VanZ from E. faecium. • vanZ1 is induced by the host antimicrobial, LL-37, but not by teicoplanin. • VanZ1 confers low-level resistance to teicoplanin, but not to LL-37. [ABSTRACT FROM AUTHOR]