Natural antibodies are preformed antibodies that are present even in naive germ-free mice in the absence of any exogenous antigenic exposure. Consistent with their specificities for microbial antigens, natural antibodies play an important non-redundant role in the first line defense against bacterial and viral infections. On the other hand natural antibodies have also been shown to have specificities for self antigens, and therefore have been proposed to provide important homeostatic “house-keeping” functions. Many of the recognized self-antigens may in fact be stress-induced self-antigens, such as oxidation-specific epitopes that accumulate during atherogenesis as well as in many other inflammatory settings, and natural antibodies could protect from the impact of the pathological accumulation of these self-antigens. In this review we will discuss the specific example of the prototypic natural antibody T15/EO6, which is increased in atherosclerotic mice and mediates atheroprotection, and discuss the potential role of natural antibodies in atherogenesis in general.