Technical Abstract: Escherichia coli infections causing post-weaning diarrhea and edema disease are one of the most prevalent disease problems in pigs in the U.S. The strains considered primarily responsible for these infections, F4 (K88) and F18, are not well controlled by traditional prophylactic antibiotic treatments, and with worldwide concern over the use of prophylactic antibiotics in animal agriculture, the development of alternatives to conventional antibiotics is urgently needed to protect swine from these E. coli infections. Colicins have been shown effective against other pathogenic E. coli strains, but their efficacy against the E. coli strains responsible for post-weaning diarrhea and edema disease has not been examined. The efficacy of two pore-forming colicins, E1 and N, against E. coli F4 (K88) and F18 were determined quantitatively in vitro. Both colicins were effective against both strains of E. coli, however their efficacy varied greatly. Colicin E1 was more effective against F18 than F4 (K88), requiring approximately 1 ug/mL of culture to completely inhibit the growth of F18 and an approximately 50 ug/mL to inhibit the growth of F4 (K88). Colicin N was less effective than Colicin E1 against E. coli F18, requiring fifty fold higher concentrations in order to achieve the same level of growth inhibition, but more effective against the F4 (K88) strain, requiring half the concentration of Colicin E1 to obtain the same growth inhibition. These antimicrobial peptides may provide an effective and environmentally sound means for the prevention of post-weaning diarrhea and edema disease in swine.