Infections caused by carbapenemase-producing Klebsiella pneumoniae are emerging causes of morbidity and mortality worldwide. Optimal treatment for non-carbapenemase-producing carbapenem-resistant K pneumoniae (nCP-CRKP) bacteremia remains undefined. The goal of this study was to assess the clinical outcome, predictors of mortality, and therapeutic strategy of carbapenems for nCP-CRKP bacteremia. A retrospective study of monomicrobial bacteremia caused by nCP-CRKP, at a medical center between 2010 and 2015 was conducted. CRKP which was defined as a minimum inhibitory concentration (MIC) of ≥ 2 for ertapenem or ≥ 4 mg/L for meropenem, or imipenem. Multiplex polymerase chain was applied to detect carbapenemase genes. The patients definitively treated with combination therapy were compared with monotherapy using a propensity score-matched analysis to assess therapeutic effectiveness. The primary end point was the 30-day crude mortality and clinical prognostic factors were assessed. Overall 171 patients met criteria were eligible for the study and their overall 30-day mortality rate was 38.6%. The multivariate logistic regression analysis showed that combination therapy was associated with a lower 30-day mortality rate (adjusted odds ratio [aOR], 0.11; 95% CI, 0.03-0.43; P = 0.001) and less clinical (aOR, 0.21; 95% CI, 0.08-0.58; P = 0.003) and microbiologic (aOR, 0.36; 95% CI, 0.19-0.71; P = 0.003) failure. However, the 30-day mortality rate in the cases infected by a pathogen with a meropenem MIC ≤8 mg/L receiving carbapenem-containing or carbapenem-sparing combination regimens was similar (15 of 58 [25.9%] vs 5 of 20 [23.3%]; P = 1.0). Combination therapy, regardless of carbapenem-containing or carbapenem-sparing, with one or more active agents improved survival more than monotherapy and was more effective in patients with critical illness. (Clin Ther. 2020; 42:XXX-XXX) © 2020 Elsevier HS Journals, Inc.