Shigella spp. infect approximately 450,000 persons annually in the United States, resulting in over 6,000 hospitalizations. Since 1999, the National Antimicrobial Resistance Monitoring System (NARMS) for Enteric Bacteria has tested every 10th Shigella isolate from 16 state or local public health laboratories for susceptibility to 15 antimicrobial agents. From 1999 to 2002, NARMS tested 1,604 isolates. Among 1,598 isolates identified to species level, 1,278 (80%) were Shigella sonnei, 295 (18%) were Shigella flexneri, 18 (1%) were Shigella boydii, and 7 (0.4%) were Shigella dysenteriae. Overall, 1,251 (78%) were resistant to ampicillin and 744 (46%) were resistant to trimethoprim-sulfamethoxazole (TMP-SMX). Prevalence of TMP-SMX- or ampicillin- and TMP-SMX-resistant Shigella sonnei isolates varied by geographic region, with lower rates in the South and Midwest regions (TMP-SMX resistance, 27% and 30%, respectively; ampicillin and TMP-SMX resistance, 25% and 22%, respectively) and higher rates in the East and West regions (TMP-SMX resistance, 66% and 80%, respectively; ampicillin and TMP-SMX resistance, 54% and 65%, respectively). Nineteen isolates (1%) were resistant to nalidixic acid (1% of S. sonnei and 2% of S. flexneri isolates); 12 (63%) of these isolates had decreased susceptibility to ciprofloxacin. One S. flexneri isolate was resistant to ciprofloxacin. All isolates were susceptible to ceftriaxone. Since 1986, resistance to ampicillin and TMP-SMX has dramatically increased. Shigella isolates in the United States remain susceptible to ciprofloxacin and ceftriaxone.