To evaluate the potential of outer membrane proteins of Haemophilus influenzae as a vaccine, sera from 11 healthy persons and from 23 patients convalescing from disease caused by Haemophilus influenzae type b were assayed for antibodies to individual outer membrane proteins of a single type b isolate, strain Eag, by a gel radioimmunoassay. All 23 patients, ranging in age from 2 months to 62 years, with 17 patients being 24 months or less, had antibodies to some of these proteins in their sera (range, antibodies to 4 to 17 proteins per patient). Although the intensity and spectrum of the response varied, all patients had antibodies to one particular outer membrane protein and 19 patients had antibodies to another, with those patients 5 years and older having antibodies to more proteins than did infants (<==24 months). In the two cases examined, convalescent sera had greater amounts and broader spectra of antibodies than did acute sera. In addition, 10 of 11 healthy subjects not known to have had systemic H. influenzae disease also had antibodies to individual outer membrane proteins, with older children having greater amounts than did their younger siblings and with children showing a different spectrum of response than that for adults. Thus, antibodies to outer membrane proteins are commonly found in humans. Also, these results and those demonstrating that hyperimmune rabbit antisera to strain Eag reacted with each of five type b substrains possessing some different outer membrane proteins indicate considerable cross-reactivity among these proteins. These results encourage continued consideration of outer membrane proteins in a vaccine.