Complement, complement receptors and natural antibody (IgM) are important factors in the immune response against pathogens. Previous studies have indicated a role for C3, the complement receptors CD35/CD21 (CR1/CR2), and IgM in the immune response to influenza virus. Nevertheless, their contribution to the long-term memory response to this pathogen remains unknown. To elucidate this role, we characterized the secondary response on mice deficient of CR1/CR2 (Cr2-/-), C3 (C3-/-), secreted IgM (micros-/-) and the double knockout C3-/-micros-/-. Overall, our results suggest that C3, IgM and CR1/CR2 play crucial roles in the maintenance of long-term memory to influenza virus, possibly through the development of memory B cells and long-term antibody secretion.