Chronic, overwhelming pulmonary infection with Pseudomonas aeruginosa is a frequent problem in patients with cystic fibrosis. Titers of antibody to the outer-membrane proteins of P aeruginosa were 10(1)-10(8) (as measured by an enzyme-linked immunosorbent assay) in the sera of 32 patients with cystic fibrosis. Fifteen patients who had been colonized with P aeruginosa for 18 months to nine years had a geometric mean antibody titer of 1.3 X 10(5)--a value approximately 500-fold higher than that for 13 patients with cystic fibrosis who had never been colonized or for 16 healthy adults without cystic fibrosis (P less than 0.001). A significant correlation was observed between the presence of antibody to outer-membrane proteins and the presence of antibody to mucoid exopolysaccharide (P less than 0.002). Nineteen serum specimens from the patients with cystic fibrosis were allowed to react with Western electophoretic blots of separated outer-membrane proteins. All of these sera contained antibodies to porin protein F. In addition, antibodies to outer-membrane proteins E, H2, and I and to a variety of minor protein components were observed in many sera.