Background— Cyclooxygenase-1 (COX-1) has been implicated in the pathogenesis of atherothrombosis and is expressed by the major cell types of atherosclerotic lesions. COX-1–mediated platelet thromboxane (TX) production has been proposed to promote both early atherosclerosis and thrombosis. Here, we examined the impact of COX-1 deficiency in bone marrow–derived cells on early atherogenesis in the mouse. Methods and Results— LDL receptor (LDLR) ^−/− and apolipoprotein E (apoE) ^−/− recipient mice were lethally irradiated and transplanted with COX-1 ^−/− bone marrow. Mice reconstituted with COX-1 ^−/− marrow had nearly complete (99.7%) loss of platelet TXA ₂ and significantly suppressed levels of macrophage and urinary TXA ₂ metabolites. Serum lipid levels and lipoprotein distributions did not differ between recipients reconstituted with COX-1 ^+/+ and COX-1 ^−/− marrow. Surprisingly, the extent of atherosclerotic lesions in both LDLR ^−/− and apoE ^−/− mice reconstituted with COX-1 ^−/− marrow was increased significantly compared with control mice transplanted with COX-1 ^+/+ marrow. Peritoneal macrophages isolated from LDLR ^−/− mice reconstituted with COX-1 ^−/− marrow had increased lipopolysaccharide-induced levels of COX-2 mRNA and protein expression. Fetal liver cell transplantation studies revealed a 30% increase in atherosclerosis in COX-1 ^−/− →LDLR ^−/− mice compared with COX-1 ^+/+ →LDLR ^−/− mice, whereas the extent of atherosclerosis was unchanged in COX-1 ^−/− /COX-2 ^−/− →LDLR ^−/− mice. Conclusions— COX-1 deficiency in bone marrow–derived cells worsens early atherosclerosis in apoE ^−/− and LDLR ^−/− mice despite virtual elimination of platelet TX production. These data demonstrate that platelet TX production does not aggravate early atherosclerotic lesion formation and that upregulation of COX-2 expression in COX-1 ^−/− macrophages is proatherogenic.