Silica exposure has been associated with development of autoantibodies and systemic autoimmune disease, but mechanisms leading to these events are unknown. This study tested the hypothesis that autoantibodies associated with silica exposure may recognize epitopes on apoptotic macrophages. Serum was obtained from New Zealand mixed (NZM) mice, in which instillation of silica significantly increased production of autoantibodies. Sera were selected that were shown, by indirect immunofluorescence (IIF), to be positive or negative for antinuclear antibodies (ANA) following silica or saline exposure, respectively. Apoptosis was induced in MH-S murine macrophages using silica or cycloheximide. The ability of the autoantibodies to preferentially recognize apoptotic cells was tested using IIF and ELISA. Apoptotic cells, but not live cells, were shown to stain with serum from ANA-positive mice, but not from ANA-negative serum. In addition, binding of antibodies from ANA-positive mice was shown to be significantly greater on cellular lysates from apoptotic cells, but not necrotic or live cell lysates using an ELISA based assay. Finally, inhibition of apoptosis with a broad spectrum caspase inhibitor, Boc-D-FMK, blocked the increased binding by the autoantibodies. These results suggest that autoantibodies from mice with silica-exacerbated autoimmune responses recognize specific epitopes on apoptotic macrophages. It is therefore possible that silica-induced apoptosis may exacerbate autoimmune responses by exposing antigenic epitopes to the immune system.