Shigellosis is a major source of gastroenteritis throughout the world. Extended-spectrum β-lactamases (ESBLs), including cefotaximases (CTX-M), confer resistance to extended-spectrum cephalosporins and significantly compromise the treatment options for shigellosis, with only a single CTX-M-producing Shigella isolate previously reported in the United States. From 1999 to 2007, 3,880 Shigella isolates were screened for antimicrobial susceptibility to 14 to 17 antimicrobials by broth microdilution, and six isolates displayed decreased susceptibility to ceftriaxone. PCR analysis showed four isolates positive for the blaCTX-M-15 gene and two for the blaCTX-M-14 gene. All six blaCTX-M genes were plasmid encoded, with plasmids of incompatibility types IncI1, IncA/C, or IncFII. Pulsed-field gel electrophoresis (PFGE) analysis revealed distinct patterns for S. sonnei and S. flexneri isolates. The emergence of CTX-M-producing Shigella isolates in the United States is concerning and necessitates continued resistance surveillance.