In December 2014, PulseNet, the national molecular subtyping network for foodborne disease, detected a multistate cluster of Shigella sonnei infections with an uncommon pulsed-field gel electrophoresis (PFGE) pattern. CDC's National Antimicrobial Resistance Monitoring System (NARMS) laboratory determined that isolates from this cluster were resistant to ciprofloxacin, the antimicrobial medication recommended to treat adults with shigellosis. To understand the scope of the outbreak and to try to identify its source, CDC and state and local health departments conducted epidemiologic and laboratory investigations. During May 2014-February 2015, PulseNet identified 157 cases in 32 states and Puerto Rico; approximately half were associated with international travel. Nine of the cases identified by PulseNet, and another 86 cases without PFGE data, were part of a related outbreak of ciprofloxacin-resistant shigellosis in San Francisco, California. Of 126 total isolates with antimicrobial susceptibility information, 109 (87%) were nonsusceptible to ciprofloxacin (108 were resistant, and one had intermediate susceptibility). Travelers need to be aware of the risks of acquiring multidrug-resistant pathogens, carefully wash their hands, and adhere to food and water precautions during international travel. Clinicians should request stool cultures and antimicrobial susceptibilities when they suspect shigellosis, and counsel shigellosis patients to follow meticulous hygiene regimens while ill.