Abstract: Background: Quinolones are used against a broad range of pathogenic bacteria. It was discovered that quinolone resistance was plasmid-mediated by qnr genes (qnrA, qnrB and qnrS) and can be simply transferred between different bacterial strains. Also, the emergence of E. coli resistance to carbapenem during the therapy with imipenem and meropenem was attributed to carbapenem-hydrolyzing enzymes encoded by blaKPC gene. This work aimed to study the susceptibility and prevalence of multidrug resistant (MDR) E. coli isolates and the possible role of quinolone and carpabenem genes in E. coli resistance. Materials and Methods: Fifty clinical E. coli isolates were collected from different diagnostic centers of Mansoura University Hospitals and their antimicrobial susceptibility pattern was tested using Kirby-Bauer disc diffusion method. Out of 50 isolates, 10 MDR E. coli candidates were selected for morphological and biochemical identification as well as for the detection of the plasmid-bearing antibiotic resistant genes by PCR and protein profile in the presence of quinolone and carbapenem using SDS-PAGE. Results: The results of antimicrobial susceptibility pattern of 50 clinical E. coli isolated from urine, wound swab, blood and sputum of patients from Mansoura University Hospitals, revealed that the isolates were cefuroxim resistant (96%), cefotriaxone resistant (92%), cefaclor resistant (90%), ciprofloxacin resistant (76%), meropenem resistant (40%), imipenem resistant (30%) and amikacin resistant (16%). Plasmid profile showed that all MDR strains harbored plasmids of different sizes. Some isolates possess single sized plasmid while other had multiple plasmids with different sizes. The distribution of antibiotic resistant genes in E. coli candidates included qnrA (0%), qnrB (50%), qnrS (70%), qnrB and qnrS (20%) and blaKPC (10%). All isolates were harbored one of quinolone resistant genes. The protein pattern of the MDR E. coli with ciprofloxacin was showed 19 bands distributed as; 16 monomorphic and 3 polymorphic. Meropenem case indicated 20 bands distributed as 14 monomorphic, 5 polymorphic and 1 unique. There were 4 bands present in control and disappeared from isolates with molecular mass (122.9, 74.2, 69.8 and 55.08 kDa). Conclusion: The antimicrobial resistance is a clinical and public health problem, there is a need for monitoring the microbial trends and antimicrobial resistance patterns.