In a surveillance study of Streptococcus pneumoniae from the United States the incidence of resistance (including both resistant and relatively resistant strains) to penicillin was 37.2% when tested by the oxacillin disk-diffusion test, or 27.2% when tested by microdilution minimum inhibitory concentrations. Strains that were susceptible to penicillin by the oxacillin test were also susceptible to the third-generation cephalosporins cefotaxime, ceftriaxone, and ceftizoxime. The overall resistance (without regard to penicillin resistance) to cefotaxime was 8.8%, to ceftriaxone was 7.9%, and to ceftizoxime was 17.2%; the rates of resistance among penicillin-resistant and relatively resistant strains (combined), however, were 23.6% for cefotaxime, 21.4% for ceftriaxone, and 43.2% for ceftizoxime. The incidence of penicillin resistance and relative resistance in these pneumococcal isolates varied from one institution to another, but all institutions had these strains and the incidence varied from 4.3% to 60.9%. Having ceftizoxime, the least active of the third-generation cephalosporins, tested on the formulary did not appear to increase selection of beta-lactam-resistant strains. The increased resistance to penicillin with the concomitant increase in resistance to third-generation cephalosporins may greatly increase the difficulty of selecting optimal therapy of patients with life-threatening infections due to S. pneumoniae.