CD6 is a lymphocyte-specific scavenger receptor expressed on adaptive (T) and innate (B1a, NK) immune cells, which is involved in both fine-tuning of lymphocyte activation/differentiation and recognition of bacterial-associated molecular patterns (i.e., lipo-polysaccharide). However, evidence on CD6’s role in the physiological response to bacterial infection was missing. Our results show that induction of monobacterial and polymicrobial sepsis in Cd6/ mice results in lower survival rates and increased bacterial loads and pro-inflammatory cytokine levels. Steady state analyses ofCd6/mice show decreased levels of natural polyreactive antibodies, concomitant with decreased cell counts of spleen B1a and marginal zone B cells. Adoptive transfer of wild-type B cells and mouse serum, as well as a polyreactive monoclonal antibody improveCd6/ mouse survival rates post-sepsis. These findings support a nonredundant role forCD6 in the early response against bacterial infection, through homeostatic expansion and functionality of innate-related immune cells.