In China, the genetic environment of KPC-2 in Zhejiang and Taiwan is type B1, while Dongguan seems to be different. A total of 131 Carbapenem-resistant Enterobacteriaceae (CRE) strains were detected from the inpatients of 13 hospitals in Dongguan from January 2016 to December 2018, including 79 Klebsiella pneumoniae (60.31%), 21 Escherichia coli (16.03%), and 12 Enterobacter cloacae (9.16%). Intensive Care Unit (ICU) was the main clinical department with detectable CRE isolates. Sputum, urine, and wound secretion were the top three samples with detectable CRE. Results of drug resistance assessment revealed high drug resistance of CRE to clinical common antibacterial agents but low drug resistance to amikacin only. Additionally, KPC-2 (57 strains, 54.81%), NDM-1 (7 strains, 6.73%), and NDM-5 (2 strains, 1.92%) carbapenemases were detected in 104 CRE strains (Klebsiella pneumoniae, Escherichia coli and Enterobacter cloacae). ST11-type (49 strains, 62.03%) was the main detectable MLST in 79 carbapenem-resistant Klebsiella pneumoniae (CRKP) strains, followed by ST1-type (25 strains, 31.65%). The porins (ompK35, ompK36, and ompK37) showed high proportions of mutations (94%, 97.47%, and 100%, respectively). The dominant genetic environment of the blaKPC-2 gene was B1-type mutant (38 strains, 48.10%), followed by A-type mutant (14 strains, 17.72%). A large number of clinical CRE isolates in Dongguan exhibited strong drug resistance. Among them, ST11-type was the most prevalent in CRKP, most of which harbored KPC-2-type carbapenemase, indicating that the genetic environment of the blaKPC-2 gene is B1-type mutant and the blaKPC-2 is mainly spread through plasmids. Moreover, the proportion of the porins mutations was extremely high. In general, the prevalence of CRKP in Dongguan is different from that in other area.