The relevance of circulating immune complexes, plasma complement activation, and serum antibodies against discrete antigens of Pseudomonas aeruginosa, to the clinical course in patients with cystic fibrosis (CF) is unknown. We related these factors to outcome in 49 patients with CF colonized by P. aeruginosa, comparing 14 who died of lung disease with 35 survivors of similar age and duration of colonization, as well as 9 uncolonized patients with CF, 24 patients with other bronchorrheic lung disease, and 10 healthy control subjects. The patients with CF colonized by P. aeruginosa who died had a higher incidence of immune complexes than did survivors (71 versus 40%, p less than 0.05). Moreover, C4 activation was highly associated with immune complexes and mortality (p less than 0.001 for each). Those who died also had much higher levels of IgG antibodies to P. aeruginosa lipopolysaccharide (LPS) and exotoxin A than did survivors colonized by P. aeruginosa (p less than 0.005 and p = 0.01, respectively), whereas both groups had similar levels of P. aeruginosa sonicate, elastase, alkaline protease, and endotoxin core antibodies. We conclude that increasing levels of serum IgG antibodies to P. aeruginosa LPS and exotoxin A and the presence of systemic immune complexes and complement activation are associated with poor prognosis in CF, and may provide useful noninvasive markers for studying the possible immunopathogenesis of CF lung disease.