Campylobacter is the most common cause of bacterial gastroenteritis worldwide. This study describes regional and seasonal differences among culture-proven Campylobacter infections in The Netherlands in 2000–2004. Data were used from two ongoing projects in The Netherlands, covering 3 million and 8 million inhabitants, respectively, for surveillance of infectious diseases. The incidence of Campylobacter infection was highest in the south of The Netherlands (55.7/100 000 vs. an average of 39.1/100 000 in other regions). The incidence in urbanised areas was 41.9/100 000 vs. 32.4/100 000 in rural areas. High stable rates of resistance to fluoroquinolones (35%) were observed. Resistance to erythromycin increased from 1.9% (in 2001) to 2.7% (in 2004). The highest rates of resistance to erythromycin were found in the south. Resistance rates increased with increasing urbanisation, most obviously for fluoroquinolones (35.9% urban vs. 27.10% rural). An inverse relationship was observed between the incidence of infection (high in summer, low in winter) and resistance to both fluoroquinolones and macrolides. Resistance to fluoroquinolones was higher in travel-related infections (54%) than in endemic infections (33%). Differences in regional incidence and resistance rates of Campylobacter infections were found. Foreign travel appeared to be associated with higher resistance rates. Given the high fluoroquinolone resistance rate, empirical treatment of severe, microbiologically confirmed, Campylobacter infection with a fluoroquinolone should be discouraged, pending susceptibility testing.