The IgM antibody response to Type III pneumococcal polysaccharide (SSS-III) was assessed in F1, F2, and backcross progeny derived from high (BALB/cAnN) and extremely low (CBA/HN) responding parental strains of inbred mice. The results of these studies indicated that a major component involved in the antibody response is X-linked, i.e., carried on the X chromosome; this component determines responsiveness to SSS-III in an almost quantal or "all-or-none" manner. Other factors, presumably autosomal genes, regulate the magnitude of the antibody response produced by mice possessing the X-linked gene; these appear to influence independently the number of antibody-producing cells found after immunization and the amount of antibody made by such cells. Strains of inbred mice varied widely in their ability to respond to SSS-III. Responsiveness was not associated with H-2 histocompatibility type. The implications of these findings with respect to the genetic control of the antibody response to SSS-III are discussed.