We examined the effect of azithromycin (AZM), a 15-membered azalide newly synthesized from erythromycin (EM), on serum sensitivity of 6 strains of Pseudomonas aeruginosa. Incubation for 48 h on agar with EM 12 micrograms/ml or AZM 1.6 micrograms/ml induced increased serum sensitivity in 2 of 6 strains (S-6, PA-103), but there were no changes in any strains with josamycin (JM) 12 micrograms/ml. Although EM 12 micrograms/ml induced increased serum sensitivity of S-6 after more than 36 h incubation, AZM 1.6 micrograms/ml induced increased serum sensitivity of this strain at 12 h incubation. AZM 0.8 microgram/ml (1/62.5 MIC) showed more potent activity to enhance serum sensitivity of S-6 than that of EM 12 micrograms/ml (1/8 MIC) after 48 h incubation. P. aeruginosa S-6 incubated with EM 12 micrograms/ml or AZM 1.6 micrograms/ml for 48 h was less hydrophobic than that of control bacteria, but there was little change in the hydrophobicity of the strain incubated with JM 12 micrograms/ml. These results show that AZM has more potent activity to enhance serum sensitivity of P. aeruginosa than that of EM. Since decrease of cell surface hydrophobicity of P. aeruginosa S-6 was correlated with increased serum sensitivity, EM and AZM may induce enhanced serum sensitivity by changing cell surface structure of P. aeruginosa.