The exopolysaccharide (EPS) of Pseudomonas aeruginosa was found to significantly inhibit neutrophil random movement, chemotaxis and degranulation at concentrations as low as 0.3 microgram/ml. Neutrophil adherence, respiratory burst and bactericidal capacity were inhibited by EPS concentrations of greater than or equal to 3 micrograms/ml. Similarly, mitogen-induced lymphocyte transformation was more sensitive to the inhibitory effects of EPS than natural-killer cell cytotoxicity. These results cannot be explained by simple mechanical blockade, as additions of EPS as late as 48 h after the initiation of lymphocyte cultures still resulted in a significant inhibition of lymphocyte transformation. However, the inhibitory effects of EPS can be reversed by extensive washing of treated lymphocytes. These results suggest that the propensity of mucoid P. aeruginosa to persist in cystic fibrosis may be explained in part by the ability of EPS to interfere with host immunity.