Versican, a chondroitin sulfate proteoglycan (CSPG), is an integral component of the extracellular matrix (ECM) necessary for embryonic development, but thereafter is expressed in very low levels in healthy adult lungs. As a key component of the extracellular matrix (ECM), versican modulates the innate immune response through interactions with other extracellular matrix molecules, regulating cell migration and influencing the accumulation and release of cytokines and growth factors. An essential feature of versican is that its impact is highly contextual. Among other factors, the influence of versican depends on the cellular source, specific agonist, and phase of the inflammatory response. Although previous work from our group shows versican has both pro and anti-inflammatory effects, the influence on pulmonary function, inflammation, and injury is not well understood. Here, we investigated the role of macrophage-derived versican in a mouse model of LPS-induced lung injury. We demonstrate that bone marrow-derived macrophages (BMDMs) and mice deficient in macrophage-derived versican show an altered acute immune response to Toll-Like Receptor-4(TLR4) activation compared to wild-type (WT) controls. The significance of these findings is furthered by histologic evidence that a lack of macrophage-derived versican contributes to increased leukocyte recruitment at 48 hours post-challenge. This study demonstrates that versican is an immunomodulatory molecule and controls the innate immune system.