Six strains of ampicillin-resistant Haemophilus influenzae type b were studied in vitro for synergy between ampicillin and nafcillin. The minimal inhibitory concentrations for these strains with 10(4) colony-forming units per ml were 6.25 to 12.5 microgram of ampicillin per ml and 6.25 to 25 microgram of nafcillin per ml. Studies with these agents demonstrated synergism against all six strains of H. influenzae type b. Most strains were inhibited by 0.78 microgram of nafcillin plus 0.78 microgram of ampicillin per ml. A child with osteomyelitis caused by H. influenzae type b was successfully treated with a combination of ampicillin and nafcillin. These data suggest that further studies assessing the synergistic effect of this drug combination against H. influenzae type b are warranted.