Shigellosis is the third most common enteric bacterial infection in the United States. Although infection is typically self-limiting, empiric treatment is often prescribed. Because of increasing antimicrobial resistance to Shigella, empiric treatment options are decreasing. Identifying resistance patterns can inform empiric treatment recommendations. The goals of our study were to examine risk factors associated with antimicrobial resistance of Shigella and examine issues related to empiric treatment and antimicrobial resistance of Shigella. During June 2006-February 2009, we attempted to interview all New York City patients reported to have shigellosis. Their Shigella isolates were tested for antimicrobial susceptibility to examine the level of resistance and identify risk factors for resistance. Analysis was conducted on two groups distinguished by a large outbreak that was documented during the data collection period. Of the 477 nonoutbreak patients, 333 (70%) patients reported taking an antibiotic for shigellosis and 36 (11%) were treated with an antibiotic to which their Shigella infection was resistant. Among this group, high levels of antimicrobial resistance were detected to amoxicillin-clavulanate (66%), ampicillin (68%), and trimethoprim-sulfamethoxazole (66%). Non-travel-associated ciprofloxacin-resistant Shigella (five patients) and ciprofloxacin-resistant Shigella sonnei (four patients) were reported for the first time to our knowledge. Antimicrobial resistance is significantly higher in New York City residents compared with national data. Some patients were treated with therapies that were not effective and to which the patient's Shigella infection was resistant. Shigella infections should not be treated with antibiotics unless the patient presents with severe or underlying illness and is at risk for systemic illness. When treatment is indicated, local monitoring of Shigella for antimicrobial resistance will provide local clinicians with the best guidance for effective empiric treatments.