F4+ E. coli and F18+ E. coli infections are an important threat for pig industry worldwide. Antibiotics are commonly used to treat infected piglets, but the emerging development of resistance against antibiotics raises major concerns. Hence, alternative therapies to prevent pigs from F4+ E. coli and F18+ E. coli infections need to be developed. Since cranberry previously showed anti-adhesive activity against uropathogenic E. coli, we aimed to investigate whether cranberry extract could also inhibit binding of F4+ E. coli and F18+ E. coli to pig intestinal epithelium. Using the in vitro villus adhesion assay, we found that low concentrations of cranberry extract (20 micro g or 100 micro g/ml) have strong inhibitory activity on F4+ E. coli (75.3%, S.D.=9.31 or 95.8%, S.D.=2.56, respectively) and F18+ E. coli adherence (100% inhibition). This effect was not due to antimicrobial activity. Moreover, cranberry extract (10 mg or 100 mg) could also abolish in vivo binding of F4 and F18 fimbriae to the pig intestinal epithelium in ligated loop experiments. Finally, two challenge experiments with F18+ E. coli were performed to address the efficacy of in-feed or water supplemented cranberry extract. No effect could be observed in piglets that received cranberry extract only in feed (1 g/kg or 10 g/kg). However, supplementation of feed (10 g/kg) and drinking water (1 g/L) significantly decreased excretion and diarrhea. The decreased infection resulted in a decreased serum antibody response indicating reduced exposure to F18+ E. coli.