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Methicillin‐resistant Staphylococcus aureus (MRSA) presents an increasing threat to public health, with antimicrobial resistance on the rise and infections endemic in the hospital setting. Despite a global research effort to understand and combat antimicrobial resistance, less work has focused on understanding the nuances in the immunopathogenesis of clinical strains. In particular, there is a surprising gap of knowledge in the literature pertaining to how clinical strains are recognized by dendritic cells (DCs). Here, we show that the activation of DCs is compromised in response to MRSA strains resistant to the last‐line antibiotic daptomycin. We found a significant reduction in the secretion of proinflammatory cytokines including tumor necrosis factor‐α, interleukin‐6, regulated upon activation, normal T cell expressed, and secreted and macrophage inflammatory protein‐1β, as well as decreased expression of CD80 by DCs responding to daptomycin‐resistant MRSA. We further demonstrate that this phenotype is coincident with the acquisition of specific point mutations in the cardiolipin synthase gene cls2, and, partly, in the bifunctional lysylphosphatidylglycerol flippase/synthetase gene mprF, which are genes that are often mutated in clinical daptomycin‐resistant strains. Therefore, throughout infection and antibiotic therapy, MRSA has the capacity to not only develop further antibiotic resistance, but also develop resistance to immunological recognition by DCs, because of single amino acid point mutations occurring under the selective pressures of both host immunity and antibiotic therapy. Understanding the diversity of clinical MRSA isolates and the nuances in their immune recognition will have important implications for future therapeutics and the treatment of these infections. [ABSTRACT FROM AUTHOR]