Shigellae have been shown to be highly susceptible to new quinolone agents, with average MICs for 90% of isolates of < 0.1 μg/ml. Because these agents also reach high concentrations in the stool after a single dose, the effectiveness of a single 800-mg dose of norfloxacin and of 5-day treatment with trimethoprim-sulfamethoxazole (TMP-SMX) were compared in a randomized trial. Patients with clinical dysentery received one of the these treatment regimens, and clinical data and follow-up culture results were analyzed for patients whose stool culture on presentation grew shigellae. When 55 patients with shigellosis (26 treated with TMP-SMX, 29 treated with norfloxacin) whose bacterial isolates were susceptible to the antibiotic given were compared by treatment group, no significant differences were seen in days of illness (mean, 2.5 ± 0.65 days with TMP-SMX and 2.0 ± 0.47 days with norfloxacin; P = 0.200) or number of unformed stools after starting treatment (mean, 9.7 ± 2.37 stools with TMP-SMX and 7.6 ± 3.19 stools with norfloxacin; P = 0.312). Resistance in vitro to TMP-SMX was seen in 15% of Shigella isolates, whereas none was resistant to norfloxacin. Bacteriologic failure was found in 1 patient among 24 receiving TMP-SMX and in none of 25 patients receiving norfloxacin. One single dose of norfloxacin was as effective as 5 days of treatment with TMP-SMX in these adults with shigellosis.