The role of the classical complement pathway in humoral immune responses was investigated in gene-targeted C1q-deficient mice (C1qA^−/−). Production of antigen-specific immunoglobulin (Ig)G2a and IgG3 in primary and secondary responses to T cell–dependent antigen was significantly reduced, whereas IgM, IgG1, and IgG2b responses were similar in control and C1qA^−/− mice. Despite abnormal humoral responses, B cells from C1qA^−/− mice proliferated normally to a number of stimuli in vitro. Immune complex localization to follicular dendritic cells within splenic follicles was lacking in C1qA^−/− mice. The precursor frequency of antigen-specific T cells was similar in C1qA^−/− and wild-type mice. However, analysis of cytokine production by primed T cells in response to keyhole limpet hemocyanin revealed a significant reduction in interferon-γ production in C1qA^−/− mice compared with control mice, whereas interleukin 4 secretion was equivalent. These data suggest that the classical pathway of complement may influence the cytokine profile of antigen-specific T lymphocytes and the subsequent immune response.