Environmental crystalline silica exposure has been associated with formation of autoantibodies and development of systemic autoimmune disease, but mechanisms leading to these events are unknown. Silica exposure in autoimmune prone New Zealand mixed (NZM) mice results in a significant exacerbation of systemic autoimmunity as measured by increases in autoantibodies and glomerulonephritis. Previous studies have suggested that silica-induced apoptosis of alveolar macrophages (AM) contributes to the generation of the autoantibodies and disease. Rottlerin has been reported to inhibit apoptosis in many cell types, possibly through direct or indirect effects on PKC. In this study rottlerin reduced silica-induced apoptosis in bone marrow-derived macrophages as measured by DNA fragmentation. In NZM mice RNA and protein levels of PKC were significantly elevated in AM, 14 weeks following silica exposure. Therefore, rottlerin was used to reduce apoptosis of AM and evaluate the progress of silica-exacerbated systemic autoimmune disease. Fourteen weeks following silica exposure, NZM mice had increased levels of anti-histone autoantibodies, high proteinuria and glomerulonephritis. However, silica instilled mice that also received weekly instillations of rottlerin had significantly lower levels of proteinuria, anti-histone autoantibodies, complement C3 and IgG deposition within the kidney. Weekly instillations of rottlerin in silica instilled NZM mice also completely inhibited the upregulation of PKC in alveolar macrophages. Taken together, these data demonstrate the in vivo treatment with rottlerin significantly decreased the exacerbation of autoimmunity by silica exposure.