A retrospective analysis was performed to measure the incidence of pneumococcal bacteremia and to identify risk factors for penicillin resistance and prognostic factors for outcome in adults. A total of 151 cases of pneumococcal bacteremia were identified from 149 adults during the period 1996–2000. The overall rate of penicillin resistance was 49%, ranging from 54.2% in 1996 to 48.5% in 2000 (P=0.93). Rates of resistance to ceftriaxone, clindamycin, erythromycin, and trimethoprim-sulfamethoxazole were 21.6%, 51%, 62%, and 44.7%, respectively. Multidrug resistance was documented in 47.7% of the cases. Penicillin resistance was significantly associated with solid tumor, biliary drainage catheter, and previous β-lactam therapy in the univariate analysis. However, the associations were not as significant as independent risk factors in the multivariate analysis. Mortality was 23.8% and did not change significantly during the study period (P=0.06). Mortality rates in cases caused by penicillin-susceptible Streptococcus pneumoniae and penicillin-resistant Streptococcus pneumoniae were 23% and 24.7%, respectively (P=0.81). Mortality was not significantly influenced by penicillin resistance, even high-level resistance (24.4% vs. 20%; P=0.64). Multivariate analysis revealed that antineoplastic chemotherapy, respiratory failure, and acute renal failure were independent prognostic factors for mortality. In conclusion, the rate of penicillin resistance among pneumococcal blood isolates was high in the late 1990s, but penicillin resistance, and even high-level penicillin resistance, was not significantly associated with increased mortality in adults with pneumococcal bacteremia.