Background. Campylobacter causes >1 million infections annually in the United States. Fluoroquinolones (e.g., ciprofloxacin) are used to treat Campylobacter infections in adults. Although human infections with ciprofloxacin-resistant Campylobacter have become increasingly common, the human health consequences of such infections are not well described. Methods. A case-control study of persons with sporadic Campylobacter infection was conducted within 7 Food Net sites during 1998–1999. The E-test system (AB Biodisk) was used to test for antimicrobial susceptibility to ciprofloxacin; ciprofloxacin resistance was defined as a ciprofloxacin minimum inhibitory concentration of ⩾4 μg/mL. We conducted a case-comparison study of interviewed persons who had an isolate tested. Results. Of 858 isolates tested, 94 (11%) were ciprofloxacin resistant. Among 290 persons with Campylobacter infection who did not take antidiarrheal medications, persons with ciprofloxacin-resistant infection had a longer mean duration of diarrhea than did persons with ciprofloxacin-susceptible infection (9 vs. 7 days [P=.04]). This difference was even more pronounced among the 63 persons who did not take antidiarrheal medications or antimicrobial agents (12 vs. 6 days [P=.04]). In a multivariable analysis-of-variance model, the persons with ciprofloxacin-resistant infection had a longer mean duration of diarrhea than did the persons with ciprofloxacinsusceptible infection (P=.01); this effect was independent of foreign travel. The association between ciprofloxacin resistance and prolonged diarrhea is consistent across a variety of analytical approaches. Conclusions. Persons with ciprofloxacin-resistant Campylobacter infection have a longer duration of diarrhea than do persons with ciprofloxacin-susceptible Campylobacter infection. Additional efforts are needed to preserve the efficacy of fluoroquinolones.