During 1997, Oklahoma City's Hospital A reported penicillin-nonsusceptible Streptococcus pneumoniae in almost 67% of isolates. To confirm this finding, all Hospital A S. pneumoniae isolates from October 23, 1997, through February 19, 1998, were tested for antibiotic susceptibility and repeat-tested at two other hospital laboratories. Medical records of Hospital A patients with invasive S. pneumoniae infections during 1994 through 1997 were also reviewed. These data were compared with 1998 statewide sentinel hospital surveillance data for invasive S. pneumoniae. Of 48 S. pneumoniae isolates from Hospital A during October 23, 1997, through February 19, 1998, 31 (65%) were penicillin-nonsusceptible S. pneumoniae, and 23 (48%) were highly penicillin resistant. Similar prevalences were confirmed at the other hospital laboratories; however, significant interlaboratory differences were noted in the determination of third-generation cephalosporin susceptibility. During 1994 through 1997, a trend toward increasing penicillin nonsusceptibility (p <0.05) was noted among S. pneumoniae isolates from nursing home patients. During 1998, 85 (30%) of 282 invasive isolates reported to the state surveillance system were penicillin-nonsusceptible S. pneumoniae; 33 (12%) were highly resistant. The increase in resistance observed is notable; the interlaboratory discrepancies are unexplained. To respond, a vaccination program was implemented at Hospital A, and vaccination efforts were initiated at nursing homes.