High-level penicillin resistance has been associated with treatment failure in patients with Streptococcus pneumoniae infections. To identify a subgroup of patients at low risk for high-level penicillin-nonsusceptible S. pneumoniae bacteremia, a cross-sectional study of 303 patients was performed. For the total study population, penicillin resistance was observed in 98 (32%) of 303 patients; high-level resistance was seen in 33 (11%). A predictive model was created by using 3 baseline variables that were independently associated with high-level penicillin resistance: previous β-lactam antibiotic use, previous stay in a risk area (defined as stay in day care facilities, prisons, homeless shelters, nursing homes, or other long-term care facilities), and previous respiratory tract infection. The model was used to identify patients at low and high risk for high-level penicillin-resistant pneumococcal bacteremia. None of the isolates of patients in the low-risk subgroup had ceftriaxone resistance. Patients in the low-risk subgroup could be empirically treated with fluoroquinolone-sparing regimens.