Bacterial sepsis is a serious life-threatening condition caused by an excessive immune response to infection. B-1 cells differ from conventional B-2 cells by their distinct phenotype and function. A subset of B-1 cells expressing CD5, known as B-1a cells, exhibits innate immune activity. Here we report that B-1a cells play a beneficial role in sepsis by mitigating exaggerated inflammation through a novel mechanism. Using a mouse model of bacterial sepsis, we found that the numbers of B-1a cells in various anatomical locations were significantly decreased. Adoptive transfer of B-1a cells into septic mice significantly attenuated systemic inflammation and improved survival, whereas B-1a cell–deficient CD19–/– mice were more susceptible to infectious inflammation and mortality. We also demonstrated B-1a cells produced ample amounts of IL-10 which controlled excessive inflammation and the mice treated with IL-10–deficient B-1a cells were not protected against sepsis. Moreover, we identified a novel intracellular signaling molecule, cAMP-response element binding protein (CREB), which serves as a pivotal transcription factor for upregulating IL-10 production by B-1a cells in sepsis through its nuclear translocation and binding to putative responsive elements on IL-10 promoter. Thus, the benefit of B-1a cells in bacterial sepsis is mediated by CREB and the identification of CREB in B-1a cells reveals a potential avenue for treatment in bacterial sepsis.