Extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli isolates were obtained from hospitalized and nonhospitalized patients in Belgium between August 2006 and November 2007. The antimicrobial susceptibility of these isolates was determined and their ESBL genes were characterized. Clonal relationships between the CTX-M-producing E. coli isolates causing urinary tract infections were also studied. A total of 90 hospital- and 45 community-acquired cephalosporin-resistant E. coli isolates were obtained. Tetracycline, enrofloxacine, gentamicin, and trimethoprim-sulfamethaxozole resistance rates were significantly different between the community-onset and hospital-acquired isolates. A high diversity of different ESBLs was observed among the hospital-acquired E. coli isolates, whereas CTX-M-15 was dominating among the community-acquired E. coli isolates (n = 28). Thirteen different pulsed-field gel electrophoresis profiles were observed in the community-acquired CTX-M-15-producing E. coli, indicating that multiple clones have acquired the bla(CTX-M-15) gene. All community-acquired CTX-M-15-producing E. coli isolates of phylogroups B2 and D were assigned to the sequence type ST131. The hospital-acquired CTX-M-15-producing E. coli isolates of phylogroups B2, B1, A, and D corresponded to ST131, ST617, ST48, and ST405, respectively. In conclusion, CTX-M-type ESBLs have emerged as the predominant class of ESBLs produced by E. coli isolates in the hospital and community in Belgium. Of particular concern is the predominant presence of the CTX-M-15 enzyme in ST131 community-acquired E. coli.