Serum antibody against polyribosylribitol phosphate, the capsular antigen of Haemophilus influenzae type b, confers protection against experimental Haemophilus infection. Antibodies against noncapsular antigens are also protective, but the antigenic specificity of the protective antibodies remains unknown. Antilipopolysaccharide antibody was prepared by immunization of rabbits with boiled H. influenzae type b cells. Antilipopolysaccharide antibodies present in these sera did not protect against experimental Haemophilus bacteremia in infant rats. Antisera were also prepared by immunization of rabbits with live H. influenzae type b bacteria. After absorption of anticapsular and antilipopolysaccharide antibodies, these sera contained antibody to several outer membrane proteins which were accessible on the intact bacterial surface as detected by radioimmune precipitation. These absorbed sera prevented experimental Haemophilus bacteremia in infant rats. Thus, antibodies against noncapsular, non-lipopolysaccharide determinants, possibly against one or more outer membrane proteins, confer protection against experimental H. influenzae type b disease. In contrast, antibodies against lipopolysaccharide are ineffective.