A nationwide sample of Shigella isolates was collected and tested for resistance to 12 antimicrobial agents to assess the prevalence and epidemiologic correlates of antimicrobial resistance in Shigella. Of the isolates, 32% were resistant to ampicillin, 7% to trimethoprim-sulfamethoxazole, and 0.4% to nalidixic acid. Fifty (20%) of 252 isolates were associated with foreign travel. The best predictor of clinically important resistance was a history of foreign travel: 20% of isolates from foreign travelers showed trimethoprim-sulfamethoxazole resistance, compared with only 4% of isolates from those without such a history. Quinolone resistance was not identified in travel-related isolates, and quinolones may be more appropriate for initial therapy of travel-related shigellosis than is trimethoprim-sulfamethoxazole.