The effects of the combination of E-1040, a new cephalosporin, ceftazidime, cefpirome, or cefepime with tobramycin against 40 Pseudomonas aeruginosa and 16 P. cepacia isolates from cystic fibrosis patients were examined. Synergy fractional inhibitory concentration less than or equal to 0.5 was found against P. aeruginosa when tobramycin was combined with E-1040 32%, cefpirome 32%, cefepime 22%, and ceftazidime 22%. Fifty-two percent of isolates showed an additive response for E-1040, 60% for cefpirome, 45% cefepime, and 55% ceftazidime, p greater than 0.05. The differences were not statistically significant. Synergy was not more likely to be achieved if the isolates were susceptible or resistant to either the aminoglycoside or cephalosporin. None of the E-1040-resistant isolates, all of which were tobramycin-resistant, became susceptible when tested with an aminoglycoside, whereas 15 of 34 cefpirome-resistant, 13 of 30 cefepime-resistant, and seven of 14 ceftazidime-resistant isolates became susceptible. Synergy of aminoglycoside and the cephalosporins against P. cepacia was found for 25% with E-1040, 44% with cefpirome, 38% with cefepime, and 31% with ceftazidime. These differences were not statistically significant.