Many studies have described an association between monocytosis and cardiovascular disease. This paper reports a mechanistic link between hypercholesterolaemia and monocytosis that helps to explain their combined effects on atherosclerosis. In the apolipoprotein E-deficient (Apoe−/−) mouse model of atherosclerosis, feeding a high-cholesterol diet results in increased proliferation of haematopoietic stem and multipotential progenitor cells (HSPCs), monocytosis and the increased entry of monocytes into atherosclerotic lesions, thereby enlarging the lesions. In wild-type mice, the authors observed high levels of APOE bound to proteoglycans on the surface of HSPCs, and this suppressed the proliferation of HSPCs in a cell-autonomous manner — probably by promoting cholesterol efflux from HSPCs. The results indicate that, in mice on a high-fat diet, a lack of cholesterol efflux from Apoe−/− HSPCs leads to membrane cholesterol accumulation and cell proliferation; this could be suppressed by the addition of the potent cholesterol acceptor high-density lipoprotein.