Background Risk factors and outcomes associated with carbapenem-resistant Enterobacteriaceae (CRE) acquisitions, are derived primarily from cohorts consisting of carbapenemase-producing (CP) strains. Worldwide epidemiology of non-CP-CRE is evolving, but controlled epidemiological analyses are lacking. Methods A matched case-case-control investigation was conducted at Shamir (Assaf Harofeh) Medical Center, Israel, 11/2014-12/2016. Non-CP-CRE (as defined by CLSI) carriers, were matched to patients with non-CRE Enterobacterales and to uninfected controls (1:1:1 ratio). Matched and non-matched multivariable regression models were constructed in order to analyze predictors for acquisition, and the independent impact of carriage on multiple outcomes, respectively. Representative isolates were whole genome sequenced and analyzed for resistome and phylogeny. Results Non-CP-CRE carriers (n=109) were matched to the two comparative groups (overall n=327). Recent exposure to antibiotics (but not specifically to carbapenems), prior ICU admission, and chronic skin ulcers, were all independent predictors for non-CP-CRE acquisition. Acquisitions were almost exclusively associated with asymptomatic carriage (n=104), and despite strong associations per univariable analyses, none were independently associated with worse outcomes. Genomic analyses of 13 representative isolates revealed polyclonality, confirmed the absence of carbapenemases, but the co-existence of multiple other genes contributing to carbapenem-resistance phenotype (multiple beta-lactamases and efflux pumps). Conclusions Non-CP-CRE acquisitions are primarily associated with asymptomatic carriage, specifically among prone populations with extensive recent exposures to antibiotics. The prevalent mode of acquisition is "emergence of resistance" (not "patient-to-patient transmission"), and therefore the role of stewardship interventions in reducing the spread of these therapeutically challenging pathogens, should be further explored.