Introduction: To characterize extended-spectrum β-lactamases (ESBLs) and plasmid-mediated quinolone resistance (PMQR) genes in Escherichia coliisolates obtained from extra-intestinal samples in three Uruguayan hospitals.Methodology: Fifty-five ESBL-producing E. coliisolates were studied. Virulence genes, ESBLs, and PMQR genes were detected by polymerase chain reaction. ESBL-producing isolates were compared by pulsed-field gel electrophoresis. Multi-locus sequence typing was also performed on 13 selected isolates.Results: Thirty-seven isolates harbored blaCTX-M-15(67.3%), eight blaCTX-M-2(14.6%), five blaCTX-M-14(9.1%), three carried both blaCTX-M-2 andblaCTX-M-14, one blaCTX-M-9, and oneblaCTX-M-8. Among the CTX-M-15 producers, 92% belonged to sequence types ST131 and ST405, and carried aac(6’)Ib-cras well. Isolates harboring blaCTX-M-2, blaCTX-M-14, blaCTX-M-9,or blaCTX-M-8were found to be genetically unrelated.Conclusions: The successful dissemination of CTX-M-15-producing E.coli isolates seems to be linked to the spreading of high-risk clones and horizontal gene transfer. A trade-off between carrying more antibiotic resistance and less virulence-related genes could partially account for the evolutionary advantages featured by successful clones.