Toxic oxygen species and several proinflammatory cytokines are involved in the pathogenesis of silicosis. In order to understand whether factors that lead to susceptibility to ozone are also important in silicosis or not, we examined ozone-sensitive C57BL/6J mice and ozone-resistant C3H/HeJ mice as models of silicosis. We also analyzed the production of proinflammatory cytokines in both the acute and the chronic phases. On Day 2 after silica injection, the ozone-resistant C3H/HeJ mice showed significantly higher cellular responses as recognized by bronchoalveolar lavage (BAL) cell counts than did the C57BL/6J mice. In the chronic phase (Day 28 after silica injection), the ozone-sensitive C57BL/6J mice showed significantly greater responses to instilled silica judged by total protein and cell number in BAL fluid, hydroxyproline content, and histology than the ozone-resistant C3H/HeJ mice. TNF-alpha production by BAL cells after silica exposure was significantly higher in C57BL/6J mice than in C3H/HeJ mice in the chronic phase, whereas there was no significant difference in IL-1 alpha production between both strains of silica-injected mice. Also, the control C57BL/6J mice had significantly higher secretions of TNF-alpha than did the control C3H/HeJ mice in the acute phase. These results suggest that ozone-sensitive C57BL/6J mice are also more susceptible to silicosis than are ozone-resistant C3H/HeJ mice, and that the initial lower cellular responses and increase in TNF-alpha production may be related to the higher level of inflammatory and fibrotic response in the C57BL/6J mice.