Background. Approximately 15-20% of Streptococcus pneu moniae clinical isolates in the United States are not susceptible to penicillin. Isolates with a minimum inhibitory concentration (MIG) of 0.12-1.0 mg/ml are intermediately resistant, and those with an MIC >2.0 mu g/ml are classified as having high-level penicillin resistance. Purpose. We determined the proportion of penicillin-resistant S. pneumoniae recovered from ocular and periocular infections from 1976 through 1995, compared these cases with penicillin-susceptible controls, and evaluated the susceptibility of penicillin-resistant isolates to selected cephalosporins and fluoroquinolones. Methods. MICs for cephalothin, ceftazidime, ciprofloxacin, and ofloxacin were determined for available isolates by the E test. We performed a case-comparison study to evaluate differences between patients with penicillin-susceptible and -nonsusceptible ocular pneumococcal infections. Results. Of 173 ocular isolates of S. pneumoniae isolated in the 20-year period, 12 (7%) were not susceptible to penicillin, including eight (5%) intermediate isolates and four (2%) highly resistant isolates. Penicillin-intermediate and -resistant pneumococci were recovered at a rate of none of 46 isolates from 1976 through 1980, one (4%) of 25 from 1981 through 1985, one (2%) of 51 from 1986 through 1990, and 10 (20%) of 51 from 1991 through 1995 (p < 0.0004). We found no significant differences in presenting characteristics between patients with ocular infections due to penicillin-susceptible pneumococci and those caused by nonsusceptible strains. All retested isolates with intermediate susceptibility to penicillin had a cephalothin MIC less than or equal to 1.5 mu g/ml, and all retested isolates with high-level penicillin resistance had a cephalothin MIC greater than or equal to 4 mu g/ml. The ceftazidime MIC for all penicillin-resistant isolates was greater than or equal to 24 mu g/ml. All penicillin-nonsusceptible isolates had MICs less than or equal to 1.5 mu g/ml for ciprofloxacin and less than or equal to 3 mu g/ml for ofloxacin. Conclusion. Penicillin resistance has recently emerged among ocular S. pneumoniae. Cephalothin, ciprofloxacin, and ofloxacin have good activity against some ocular isolates with intermediate penicillin susceptibility, although another agent such as vancomycin may be needed for pneumococci with high-level penicillin-resistance.