Previous studies revealed that protozoa (amoebae) can augment the virulence (ability to cause disease) of certain Salmonella strains that are resistant to multiple antibiotics. This phenomenon has not yet been observed in swine because many of these strains have low virulence in domestic pigs. However, resistance to multiple antibiotics was recently discovered in Salmonella choleraesuis, a strain that causes the most severe type of disease in swine. Enhancing virulence in Salmonella choleraesuis, would be devastating for the swine industry and this recent discovery is the basis for this project. The first objective of this project was to evaluate the possibility that protozoa can augment the virulence of multiple antibiotic resistant Salmonella choleraesuis. The second objective was to determine the best antibiotic for treating this infection. The research involved evaluating the ability of protozoa to enhance Salmonella choleraesuis in the laboratory and in swine. Laboratory studies involved measuring the ability of Salmonella choleraesuis to penetrate host cells, i.e. cellular penetration is an important part of Salmonella virulence, after exposure to protozoa. Swine studies involved orally infecting 10 day-old pigs with Salmonella choleraesuis exposed to protozoa. Swine were monitored for signs of disease and necropsies were performed in order to determine the amount of Salmonella in the animals. Some pigs were treated with either of two antibiotics: ceftiofur or amikacin. Results from these studies revealed that protozoa are capable of enhancing the cellular penetration of Salmonella choleraesuis by approximately 700%. Animal studies revealed that protozoa-exposed Salmonella choleraesuis were capable of causing disease at 24 hours earlier compared to pigs infected with Salmonella choleraesuis that had not been exposed to protozoa. Tissue samples revealed that Salmonella choleraesuis was ten times more prevalent in swine infected with Salmonella choleraesuis exposed to protozoa. Both ceftiofur and amikacin ameliorated signs of disease (fever, diarrhea, and lethargy) although ceftiofur-treated pigs had a smaller load of Salmonella choleraesuis. The results indicate that multiple antibiotic Salmonella choleraesuis can be more virulent after exposure to protozoa. Protozoa are water-borne common microbes and thus it appears that the combination of protozoa and Salmonella choleraesuis can lead to a dramatic course of Salmonella infection in swine. Ceftiofur seems to be the most appropriate treatment for this infection.