Objective— The scavenger receptors SR-A and CD36 have been implicated in macrophage foam cell formation during atherogenesis and in the regulation of inflammatory signaling pathways, including those leading to lesional macrophage apoptosis and plaque necrosis. To test the impact of deleting these receptors, we generated Apoe −/− mice lacking both SR-A and CD36 and fed them a Western diet for 12 weeks. Methods and Results— We analyzed atheroma in mice, assessing lesion size, foam cell formation, inflammatory gene expression, apoptosis, and necrotic core formation. Aortic root atherosclerosis in Apoe −/− Cd36 −/− Msr1 −/− mice, as assessed by morphometry, electron microscopy, and immunohistochemistry, showed no decrease in lesion area or in vivo foam cell formation when compared to Apoe −/− mice. However, Apoe −/− Cd36 −/− Msr1 −/− lesions showed reduced expression of inflammatory genes and morphological analysis revealed a ≈30% decrease in macrophage apoptosis and a striking ≈50% decrease in plaque necrosis in aortic root lesions of these mice. Conclusions— Although targeted deletion of SR-A and CD36 does not abrogate macrophage foam cell formation or substantially reduce atherosclerotic lesion area in Apoe −/− mice, loss of these pathways does reduce progression to more advanced necrotic lesions. These data suggest that targeted inhibition of these pathways in vivo may reduce lesional inflammation and promote plaque stability.