The objective of this study was to determine the efficacy of selected phages individually and in combination in prevention and treatment of diarrhea due to experimental O149:H10:F4 enterotoxigenic Escherichia coli (ETEC) in weaned pigs. For prophylaxis, the phages were administered orally shortly after challenge, and for therapeutic use, were given 24h after challenge, following the onset of diarrhea. The parameters used to assess outcomes were weight change, duration of diarrhea, severity of diarrhea, composite diarrhea score, and extent of shedding of the challenge ETEC over 6 days. Six phages that were tested individually in a prophylactic mode were effective as determined by a significant change in each of the parameters, although the phages were not present at titres greater than 10(3)PFU/g of feces. A modified protocol involving pre-treatment of the pigs with florfenicol and oral administration of sodium bicarbonate prior to the ETEC challenge and phage administration resulted in high levels of phages in the feces. Using this protocol, a combination of three phages that was tested in the prophylactic mode significantly reduced the severity of diarrhea and the composite diarrhea score. A mixture of two phages given therapeutically significantly improved each of the outcome parameters, without perturbation of the total fecal E. coli flora. Enumeration of phages in feces after treatment indicated that the phages were replicating to high titres in the intestinal tract of ETEC infected pigs within 1-2 days before declining progressively. These findings indicate that the selected phages were effective in moderating the course of experimental O149:H10:F4 ETEC diarrhea in weaned pigs when given prophylactically or therapeutically.