Objectives— Monocyte/macrophage recruitment and activation at vascular predilection sites plays a central role in the pathogenesis of atherosclerosis. Heterotrimeric G proteins of the G _12/13 family have been implicated in the control of migration and inflammatory gene expression, but their function in myeloid cells, especially during atherogenesis, is unknown. Approach and Results— Mice with myeloid-specific deficiency for G _12/13 show reduced atherosclerosis with a clear shift to anti-inflammatory gene expression in aortal macrophages. These changes are because of neither altered monocyte/macrophage migration nor reduced activation of inflammatory gene expression; on the contrary, G _12/13 -deficient macrophages show an increased nuclear factor-κB–dependent gene expression in the resting state. Chronically increased inflammatory gene expression in resident peritoneal macrophages results in myeloid-specific G _12/13 -deficient mice in an altered peritoneal micromilieu with secondary expansion of peritoneal B1 cells. Titers of B1-derived atheroprotective antibodies are increased, and adoptive transfer of peritoneal cells from mutant mice conveys atheroprotection to wild-type mice. With respect to the mechanism of G _12/13 -mediated transcriptional control, we identify an autocrine feedback loop that suppresses nuclear factor-κB–dependent gene expression through a signaling cascade involving sphingosine 1-phosphate receptor subtype 2, G _12/13 , and RhoA. Conclusions— Together, these data show that selective inhibition of G _12/13 signaling in macrophages can augment atheroprotective B-cell populations and ameliorate atherosclerosis.