OBJECTIVE To determine whether reduced penicillin or ceftriaxone susceptibility affects clinical presentation and outcome in children with pneumococcal bacteremia. METHODS Retrospective review of patients with Streptococcus pneumoniae bacteremia. RESULTS We reviewed 922 cases of pneumococcal bacteremia. Of 744 isolates with known penicillin (PCN) susceptibilities 56 were PCN-nonsusceptible. The majority displayed intermediate resistance; 14 of 730 isolates with known ceftriaxone (CTX) susceptibilities were CTX-nonsusceptible. Neither the PCN- nor the CTX-nonsusceptible cohort displayed a difference from its susceptible counterpart in temperature, respiratory rate or white blood cell count on initial patient evaluation, although trend suggested they were more often admitted at the initial visit. At follow-up only children treated initially with antibiotic were evaluated. Children with PCN-nonsusceptible isolates were no more likely to be febrile than those with PCN-susceptible isolates (28% vs. 25%, P = 0.61) and were no more likely to have a positive repeat blood culture (0% vs. 1%, P = 0.59) or a new focal infection (10% vs. 6%, P = 0.79). Data concerning CTX-nonsusceptible organisms were limited by the low number of such isolates. Although patients with CTX-nonsusceptible pneumococci were more likely to be febrile at follow-up than those with CTX-susceptible organisms (67% vs. 24%, P = 0.04), we were unable to demonstrate a significant difference for other endpoints. CONCLUSIONS Reduced antibiotic susceptibility does not alter the clinical presentation of pneumococcal bacteremia. With current practice intermediate resistance to PCN is of little clinical significance in nonmeningitic systemic pneumococcal infections.