Immunosuppression, impaired cytokine production and high susceptibility to secondary infections are characteristic for septic patients, and for mice after induction of polymicrobial septic peritonitis by sublethal cecal ligation and puncture (CLP). Here, we demonstrate that CLP markedly altered subsequent B‐cell responses. Total IgG and IgM levels, as well as the memory B‐cell response, were increased in septic mice, but antigen‐specific primary antibody production was strongly impaired. We found that two days after CLP, CD11b⁺ splenocytes were activated as demonstrated by the increased expression of activation markers, expression of arginase and production of NO by immature myeloid cells. The in vivo clearance of a bacterial infection was not impaired. DCs demonstrated reduced IL‐12 production and altered antigen presentation, resulting in decreased proliferation but enhanced IFN‐γ production by CD4⁺ cells. CD4⁺ T cells from mice immunized on day 2 after CLP showed reduced Th1 and Th2 cytokine production. In addition, there was an increase in Treg cells. Interestingly, levels of immature B cells decreased but levels of mature B cells increased two days after CLP. However, adoptive transfer of naïve CD4⁺ T cells, naïve B cells, or naïve DCs did not rescue the antigen‐specific antibody response.