Alveolar macrophages express the class A scavenger receptor (CD204); yet its role in vivo in lung defense against environmental particles has not been clearly defined. In the current study, CD204 null mice (129Sv background) were used to investigate the link between CD204 and the downstream events of inflammation and fibrosis following silica exposure in vivo. CD204 -/- macrophages were shown to recognize and uptake silica in vitro, although this response was attenuated compared to 129Sv wild-type mice. The production of tumor necrosis factor alpha (TNF) in lavage fluid was significantly enhanced in CD204 null mice compared to wild-type following silica exposure. Moreover, following exposure to environmental particles, CD204 -/- macrophages exhibit improved cell viability in a dose dependent manner compared to wild-type macrophages. Finally, histopathology from a murine model of chronic silicosis in129Sv wild-type mice displayed typical focal lesions, interstitial thickening with increased connective tissue matrix, and cellular infiltrate into air space. In contrast, CD204 -/- mice exhibited little to no deposition of collagen, yet demonstrated enhanced accumulation of inflammatory cells largely composed of neutrophils. Our findings point to an important role of CD204 in mounting an efficient and appropriately regulated immune response against inhaled particles. Furthermore, these results indicate that the functions of CD204 are critical to the development of fibrosis and the resolution of inflammation.