The Panton-Valentine leukocidin (PVL) is a cytotoxin expressed by many methicillin-resistant Staphylococcus aureus (MRSA) strains that cause community-acquired infections (CA-MRSA). Its role in virulence however, is controversial, with clinical data suggesting that PVL-producing strains may cause less severe disease in humans. PVL is capable of lysing human white blood cells, but at sublytic amounts, PVL can activate protective host immunity in the absence of cell damage. The concentration-dependent reactions it elicits from host cells could be the reason for seemingly contradictory results about PVL's role in virulence. We hypothesized that a key to understanding PVL's action on host cells and, possibly, outcomes from infection is the amount of toxin present, a hypothesis previously supported in studies using a low-inoculum skin infection model, where low levels of PVL augmented innate immune resistance to infection. Here, we present additional data supporting this hypothesis using a mouse model of MRSA pneumonia, wherein we found increased virulence of isogenic Δpvl strains and further confirmed PVL's capacity to activate proinflammatory responses from mouse and human neutrophils and pulmonary cells. Activation was measured as the production of phosphorylated p38 mitogen-activated protein kinase (MAPK) and proinflammatory cytokines interleukin-8 (IL-8) and KC (from human and mouse cells, respectively), as well as the release of antibacterial factors. Conversely, PVL lowered the levels of tumor necrosis factor alpha (TNF-α) produced in active pulmonary infection, while low doses induced apoptosis, suggesting that PVL also has the capacity to regulate inflammation. Our data indicate that, independent of its cytotoxic effects, PVL also plays an important and positive immunomodulatory role during MRSA infections.