BACKGROUND: Campylobacter sp. is a major cause of bacterial enterocolitis and travelers' diarrhea. Empiric treatment regimens include fluoroquinolones and macrolides. METHODS: Over the period 1994 to 2006, 724 Campylobacter jejuni/Campylobacter coli isolates recovered from international travelers at the outpatient clinic of the Institute of Tropical Medicine, Antwerp, Belgium, were reviewed for their susceptibility to norfloxacin and erythromycin. RESULTS: Norfloxacin resistance increased significantly over time in isolates from travelers returning from Asia, Africa, and Latin America. For the years 2001 to 2006, norfloxacin resistance rates were 67 (70.5%) of 95 for Asia, 20 (60.6%) of 33 for Latin America, and 36 (30.6%) of 114 for Africa. The sharpest increase was noted for India, with no resistance in 1994, but 41 (78.8%) of 52 resistant isolates found during 2001 to 2006. Erythromycin resistance was demonstrated in 20 (2.7%) isolates, with a mean annual resistance of 3.1% +/- 2.8%; resistance increased over time, with up to 3(7.5%) of 40 and 3 (8.6%) of 35 resistant isolates in 2004 and 2006, respectively (p < 0.05); there was no apparent geographic association. Combined resistance to norfloxacin and erythromycin was observed in five isolates. CONCLUSIONS: The high resistance rates to fluoroquinolones warrant reconsideration of their use as drugs of choice in patients with severe gastroenteritis when Campylobacter is the presumed cause. Continued monitoring of the incidence and the spread of resistant Campylobacter isolates is warranted.