Alpha C protein, found in 76% of non-type III strains of group B Streptococcus (GBS), elicits antibodies protective against alpha C-expressing strains in experimental animals, making it an appealing carrier for a GBS conjugate vaccine. We determined whether natural exposure to alpha C elicits antibodies in women. Geometric mean concentrations of alpha C-specific IgM and IgG were similar by ELISA in sera from 58 alpha C GBS strain colonized and 174 age-matched non-colonized women (IgG 245 and 313 ng/ml; IgM 257 and 229 ng/ml, respectively), but acute sera from 13 women with invasive alpha C-expressing GBS infection had significantly higher concentrations (IgM 383 and IgG 476 ng/ml [p=0.036 and 0.038, respectively]). Convalescent sera from 5 of these women 16-49 days later had high alpha C-specific IgM and IgG concentrations (1355 and 4173 ng/ml, respectively). In vitro killing of alpha C-expressing GBS correlated with total alpha C-specific antibody concentration. Invasive disease but not colonization elicits alpha C-specific IgM and IgG in adults.