Background Inhibitory immune receptors are important for maintaining immune homeostasis. We recently identified a member of this group, LAIR1, in advanced cutaneous T-cell lymphoma, a cancer of skin-invasive T cells associated with recurrent and often fatal S. aureus skin and soft tissue infections. Based on these data, we predicted that LAIR1 plays a role in immune response to S. aureus infection. Objective Determine the impact of LAIR1 loss on S. aureus skin infection. Methods Wild type (WT) and Lair1 knock-out (KO) mice were subjected to subcutaneous S. aureus skin infection. In skin lesions, we measured size, bacterial clearance, immune cell recruitment (flow cytometry), and cytokine production (ELISA). We compared changes in gene expression (qRT-PCR), cytokine production (ELISA), and complement-mediated phagocytosis (flow cytometry) in WT and Lair1 KO bone marrow-derived macrophages (BMDMs) infected with S. aureus. Finally, we conducted RNAseq from S. aureus skin lesions and bone marrow neutrophils and monocytes 2 and 5 days post-infection (dpi), and from in vitro-infected BMDMs. Results Lair1 KO mice had significantly larger areas of abscess and dermonecrosis by 1 dpi and decreased bacterial clearance at 2 dpi. BMDMs showed defects in proinflammatory cytokine production and complement-mediated phagocytosis. Conclusions Taken together, these data support a previously unrecognized role for LAIR1 in myeloid response to bacterial infection.