Natural antibodies, predominantly immunoglobulin M (IgM), play an important role in the defense against pathogens and in maintaining homeostasis against oxidized molecules known as oxidation-specific epitopes, such as those contained in oxidized low-density lipoproteins. However, due to the complexity of the oxidized products, very few individual epitopes have been characterized in detail. In the present study, to identify endogenous sources of oxidation-specific epitopes, we stimulated mouse spleen and peritoneal cavity (PerC) cells in vitro with bovine serum albumin (BSA) modified with a variety of lipid peroxidation-related carbonyl compounds, and identified the acrolein-modified BSA (acrBSA) as the most efficient trigger studied for the production of IgM in PerC cells. The acrolein-specific epitopes accelerated the differentiation of B-1a cells, a fetal-derived B cell lineage, to plasma cells. In addition, acrBSA was specifically bound to B-1a cells, suggesting the presence of an acrolein-specific IgM-B cell receptor (BCR). A hybridoma, RE-G25, producing an acrolein-specific IgM, was established from the PerC cells and was indeed identified as a population of B cells expressing a specific IgM-BCR. In addition, we analyzed the BCR repertoire of acrolein-specific B cells and identified the most frequent IgM heavy chain gene segments of the B cells. These data established the presence of innate B cells expressing the acrolein-specific BCR, and suggested that in addition to our understanding of acrolein as a toxic aldehyde, acrolein may play a role as a trigger of the innate immune response.