Apolipoprotein (apo) E3Leiden is a dysfunctional apo E variant associated with familial dysbetalipoproteinemia in humans. Transgenic mice carrying the APOE3Leiden gene develop hyperlipidemia and are highly susceptible to diet-induced atherosclerosis. An early step in atherosclerosis is foam cell formation, which is thought to result from the unrestricted uptake of modified lipoproteins by macrophages. To investigate the role of the macrophage scavenger receptor type I and II (MSR-A) in this process, APOE3Leiden transgenic mice were crossed onto a MSR-A deficient background and the development of atherosclerosis was examined. In view of recent results with apo E deficient mice (Suzuki H et al., A role for the macrophage scavenger receptors in atherosclerosis. Nature 1997; 386(6622):292-296), absence of the MSR-A in APOE3Leiden mice was expected to lead to a reduction of atherosclerosis. In our study we compared APOE3Leiden/MSR-A deficient mice (E3L MSR-A -/-) to APOE3Leiden/MSR-A wild-type mice (E3L MSR-A +/+). These animals were fed an atherogenic diet for 10 weeks. Quantification of the lesion area showed no significant difference between E3L MSR-A -/- and E3L MSR-A +/+ mice although there was a trend towards the development of larger lesions in the E3L MSR-A -/- mice. All lesions were typed according to their cellular composition. In both male and female E3L MSR-A -/- mice, significantly more severe lesions developed as compared to E3L MSR-A +/+ mice. These results indicate that the effect of MSR-A deficiency on atherogenesis may depend on the presence or absence of apo E.