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 10¹–10⁸ (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 × 10⁵—a value ∼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 < 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 < 0.002). Nineteen serum specimens from the patients with cystic fibrosis were allowed to react with Western electrophoretic 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.