Increasingly, drug-resistant Streptococcus pneumoniae is an identified pathogen causing pneumonia, sepsis, and meningitis. Our study evaluated outcome variables of patients infected with strains of S. pneumoniae moderately resistant to penicillin. We retrospectively analyzed the data on 110 Huntington, West Virginia, community patients who had types 6, 9, 14, 19, and 23 pneumococcal infections between 1982 and 1994. These strains are most likely to demonstrate resistance. Comparing patients infected with sensitive vs. moderately resistant pneumococcal strains, we found no significant difference in days in the hospital (10.9 vs. 11.1, P =.96), days of fever (2.4 vs. 2.8, P =.74), or mortality (21% vs. 19%, P =.15). Antibiotic selection did not significantly affect case fatality rates in the two groups—treated with penicillin or ampicillin alone, 16% vs. 11%, Odds Ratio = 1.50 ± 1.73; P =.38; treated with an antibiotic other than penicillin, 24% vs. 28%, Odds Ratio = 0.77 ± 0.69; P =.27). No significant differences occurred between groups regarding type of infectious process (P =.94). We conclude that infection with pneumococcal strains of moderate resistance to penicillin does not affect clinical outcome.