Two hundred and fifty-seven ampicillin-resistant clinical isolates of Haemophilus influenzae were tested by disk diffusion and MIC determination for susceptibility to aztreonam, imipenem, and amoxycillin combined with clavulanate. The modal MICs and MICs for 50 and 90% of isolates of all three antimicrobial agents for the 157 beta-lactamase-positive strains did not differ significantly from figures obtained with 2,201 ampicillin-susceptible H. influenzae by the same methods. Aztreonam and amoxycillin-clavulanate were less active, as reflected by an increase in these parameters, against 38 beta-lactamase-negative isolates requiring greater than or equal to 4 micrograms of ampicillin per ml for inhibition and 62 strains considered to have an intermediate degree of nonenzymic (intrinsic) resistance to ampicillin (zone diameters of less than 20 mm with 2-micrograms ampicillin disks and MICs of 1 or 2 micrograms/ml). There was no detectable difference in imipenem activity against these 100 strains compared with that observed against the ampicillin-susceptible group. Of the 24 strains requiring at least 4 micrograms of imipenem per ml for inhibition, 13 also showed reduced susceptibility to ampicillin (5 beta-lactamase-positive and 8 beta-lactamase-negative isolates). A lack of correlation between reduced susceptibility to imipenem and the other beta-lactams was observed.