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Carbapenem-resistant Klebsiella pneumoniae (CRKP) bloodstream infection (BSI) has become increasingly frequent threat recently, especially in the intensive care unit (ICU). High-dose tigecycline (TGC) regimen is proposed due to the limitation of treatment options. We investigated the efficacy and safety of high-dose TGC combination regimens for treating CRKP BSI. Furthermore, the risk factors for mortality were also determined.This was a single center retrospective cohort study conducted from 2014 to 2016. A total of 40 patients with nosocomial CRKP BSI admitted to the ICU were included; they were classified into two groups according to the treatment regimens with high-dose TGC (HD group) or not (non-HD group). In-hospital mortality rates and microbiologic responses from both groups were reviewed and compared. Besides, the survival and non-survival groups were compared to identify the risk factors of mortality.Twenty-three patients constituted the HD group (high-dosage TGC regimen was administered as 200 mg loading dose followed by 100 mg every 12 h) and 17 patients constituted the non-HD group (standard dose TGC therapy as 100 mg loading dose followed by 50 mg every 12 h and other antibiotics). The in-hospital mortality was 52.2% in the HD group and 76.5% in the non-HD group (P = .117). The Kaplan–Meier test showed significantly longer survival times in the HD group (mean: 83 days vs 28 days; P = .027). Microbiological eradication was observed in 13 patients (56.5%) in the HD group and 6 patients (36.3%) in the non-HD group (P = .184). A smaller fraction of patients in the HD group were subjected to vasoactive therapy (52.2% vs 88.2%; P = .016) compared to the non-HD group. There was no significant difference in the manifestation of adverse effects between the two groups. In the multivariate analysis, multiple organ dysfunction syndrome (MODS), vasoactive therapy, and exposure to carbapenems were regarded as the independent predictors of mortality.A therapeutic regimen consisting of a high dose of TGC was associated with significantly longer survival time and numerically lower mortality in CRKP BSI. Adverse events were not increased with the double dose therapy.