We investigated the function of Clara cells in vivo during exposure to inhaled crystalline silica by morphological and immunohistochemical examination of intra-alveolar cells and alveolar macrophages in Clara cell-ablated mice. The Clara cells of male FVB/n mice (8-12 weeks old) were ablated by intraperitoneal administration of naphthalene (300 mg/kg). The mice were then exposed to crystalline silica (Min-U-Sil-5, 97.1 ± 9.5 mg/m³, 6 hours/day, 5 days/week) for up to two weeks. The lungs were assessed by morphometry, as well as by immunohistochemistry of CD36, lectin-like oxygenated low-density lipoprotein receptor (LOX)-1, and matrix metalloproteinases (MMPs) -2, -9 and -12. There was a significantly greater number of intra-alveolar cells in Clara cell-ablated mouse groups than in wild-type mouse groups that were exposed to crystalline silica. A marked number of foamy alveolar macrophages were only detected in the Clara cell-ablated group exposed to crystalline silica, indicating that Clara cells inhibit infiltration and foam cell formation of alveolar macrophages. Immunohistochemical analysis indicated that foamy alveolar macrophages in the Clara cell-ablated group that inhaled crystalline silica overexpress CD36 and LOX-1, indicating upregulation of scavenger receptors of alveolar macrophages. These cells also express MMP-2, -9 and -12, suggesting increased gelatinolytic and elastolytic activities. Our findings suggest that Clara cells not only inhibit infiltration of alveolar macrophages but also their phagocytotic and gelatinolytic functions in silica-induced pulmonary injury.