BACKGROUND Tigecycline is regarded as a last resort treatment for carbapenem-resistant Enterobacter cloacae (CREC) infections, and increasing numbers of tigecycline- and carbapenem-resistant E. cloacae (TCREC) isolates have been reported in recent years. However, risk factors and clinical impacts of these isolates are poorly characterized. METHODS We conducted a retrospective case-case-control study of hospitalized patients with TCREC infection during the period 2012-2016 in Chongqing, China. Case patients with TCREC and those with CREC were compared to a control group with no E. cloacae infection. Multivariate logistic regression models were used to identify independent risk factors for acquiring TCREC and CREC. RESULTS A total of 36 TCREC cases, 36 CREC cases, and 100 controls were enrolled in our study. Multivariable analysis indicated that nasal catheter (OR: 8.9; 95% CI: 1.1-75.2), exposure to penicillin (OR: 95.9; 95% CI: 8.9-1038.3), aminoglycosides (OR: 42.1; 95% CI: 2.1-830.6), and fluoroquinolones (OR: 18.6; 95% CI: 1.9-185.6) were independent predictors for acquiring TCREC. In addition, venous catheterization (OR: 12.2; 95% CI: 2.5-58.5), penicillin (OR: 30.8; 95% CI: 7.9-120.0), and broad-spectrum cephalosporin (OR: 5.0; 95% CI: 1.5-17.3) were independently associated with CREC acquisition. CONCLUSIONS Reasonable antibiotic stewardship programs and surveillance are necessary to control the tigecycline resistance among high-risk patients.