Two hundred fifty-eight isolates of Streptococcus pneumoniae obtained from 232 infants and children at Children's Medical Center, Dallas, from November 1, 1981, to March 31, 1983, were screened for susceptibility to penicillin. On 1-microgram oxacillin disks 21 strains (8%) had zones of inhibition of 17 mm or less, and the tube-dilution minimal inhibitory concentrations of penicillin were from 0.125 to 0.5 micrograms/ml. These strains were designated as relatively resistant S. pneumoniae (RRSP). Prior therapy with a beta-lactam agent had occurred in 56% of patients with RRSP disease compared with 14% of randomly selected children with infections due to susceptible strains of S. pneumoniae (P = 0.009). Fifteen children (6%) had diseases due to RRSP ranging from sepsis or meningitis to otitis media or conjunctivitis. Four children, including the two patients with meningitis, had unsatisfactory responses to therapy with a beta-lactam antibiotic. Vancomycin or chloramphenicol is preferred for therapy of disease due to RRSP.