Cross-reactivity between capsular antigens of Haemophilus influenzae types a and b, and Streptococcus pneumoniae types 6A and 6B was studied by means of comparative double diffusion, quantitative precipitin tests and enzyme-linked immunosorbent assay (ELISA). Antisera against whole bacteria were employed. When capsular antigens of S. pneumoniae types 6A and 6B were compared by means of the double diffusion technique, three antigenic determinants were distinguished, two of them being common to the two serotypes. When pneumococcal capsular antigens were compared with H. influenzae capsular antigens, cross-reactive antibodies were detectable only in anti-pneumococcal sera. The heterologous pneumococcal polysaccharide preparation precipitated about 80% of the capsular antibodies in pneumococcal antisera, while heterologous H. influenzae polysaccharide precipitated only about 20-30% of the capsular antibodies in anti-H. influenzae sera. S. pneumoniae polysaccharide precipitated 10-20% of the antibodies in antisera against. H. influenzae, and H. influenzae polysaccharide precipitated about 20-25% of the antibodies in antisera against S. pneumoniae type 6A. Approximately the same degree of cross-reactivity was revealed when ELISA was employed. The absorption study of the antisera with D-ribitol-5-phosphate indicates that this structure is responsible for the cross-reactivity between S. pneumoniae and H. influenzae.