The susceptibilities of singly or multiply-resistant clinical isolates of Haemophilus influenzae were determined by agar dilution to aztreonam, imipenem, and six third-generation cephalosporins. These included selected isolates that were resistant to ampicillin only, chloramphenicol only, and four isolates that were resistant to ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole. All of the isolates were highly susceptible to these newer beta-lactam antibiotics. Isolates resistant to trimethoprim-sulfamethoxazole and/or chloramphenicol had susceptibilities similar to those of strains resistant only to ampicillin. Ceftriaxone, ceftizoxime, and cefotaxime were the most active of the study antibiotics (MIC90 = 0.004-0.016 micrograms/ml), and were also bactericidal at concentrations no more than twice the minimum inhibitory concentration (MIC). Minimum inhibitory concentrations of cefoperazone increased dramatically with only a 10-fold increase in inoculum size of beta-lactamase producing strains, while MICs of the other new agents were not significantly affected by elevation of the inoculum. These new antibiotics appear to be promising candidates for therapy of infections due to resistant H. influenzae.