Background: Treatment of gonorrhea is complicated by widespread resistance of Neisseria gonorrhoeae to antimicrobial agents of choice, including decreased susceptibility to ciprofloxacin. Goal: To demonstrate the efficacy and safety of gatifloxacin, a novel 8-methoxy fluoroquinolone antibiotic, compared with ofloxacin in treating patients with uncomplicated gonococcal infection. Study Design: In a double-blind, randomized (2:2:1), controlled trial, 340 men and 388 women with uncomplicated gonorrhea who were 16 years or older received a single oral dose of gatifloxacin (400 mg or 600 mg) or ofloxacin (400 mg). Primary analysis of efficacy was based on bacteriologic eradication from sites of infection. Secondary analyses examined clinical response and adverse event profiles. Results: Bacteriologic eradication rates for gatifloxacin in evaluable men with urethral gonorrhea were 99% (400 mg) and 100% (600 mg) versus 100% for ofloxacin (n = 117, 122, and 55, respectively: P = ns). Eradication rates in evaluable women with endocervical gonorrhea were 99% for both 400 mg and 600 mg gatifloxacin versus 100% for ofloxacin (n = 101, 104, and 55, respectively; P = ns). Eradication rates were 100% for both rectal (n = 43) and pharyngeal (n = 31) infection across all treatment groups. All three drug regimens were well tolerated and exhibited similar clinical response profiles. Conclusion: Gatifloxacin is safe and effective as a single 400-mg or 600-mg dose for the treatment of uncomplicated gonorrhea. Similar efficacy rates were observed with the 400-mg and 600-mg doses. A single 400-mg dose can be recommended for treatment of uncomplicated gonorrhea.