The bacterial pathogen Staphylococcus aureus (S. aureus) is the causative agent in a broad spectrum of diseases, ranging from localised skin and soft tissue infections to potentially lethal conditions such as necrotizing fasciitis, pneumonia and sepsis. Neutrophil granulocytes are essential for the defense against S. aureus, and the bacterium deploys a variety of virulence factors that aim to disarm the neutrophil response1,2. How these factors exert their function within tissue microenvironments is poorly understood. We show here that the staphylococcal cytotoxin alpha-hemolysin (Hla) thwarts neutrophil homing to infected skin through the specific destruction of perivascular macrophages in early infection, resulting in improved bacterial survival and tissue necrosis. Using intravital multi-photon microscopy, we found that neutrophil adherence to dermal venules and subsequent extravasation in wildtype S. aureus infected skin was markedly reduced as compared to infections with Hla-deficient S. aureus. Neutrophils emigrated from inflamed vessels in close physical contact with perivascular macrophages, which were a major source of CXCL1 and 2, chemokines implicated in neutrophil homing. Strikingly, Hla caused the rapid lysis of perivascular macrophages in situ. Our data reveal a previously unknown role of perivascular macrophages in guiding leukocyte homing to inflamed dermis, and show that killing of these cells provides a critical window for microbial immunoevasion.