An outbreak caused by a highly resistant strain of Salmonella typhimurium occurred in a nursery at a university medical center. The outbreak strain, which was resistant to ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole, was apparently imported from the Far East by a Cambodian refugee. The five patients involved had severe underlying diseases, and bacteremia and meningitis developed in one of these patients. The only reservoir identified was the gastrointestinal tracts of the infected patients, and infection was probably transmitted by the contaminated hands of hospital personnel. The outbreak was rapidly brought under control by isolating cases outside of the nursery and by instituting enteric precautions for infants who remained in the nursery. When compared by disk diffusion susceptibility tests with 353 strains of S. typhimurium tested at the Centers for Disease Control, the imported strain had a unique antibiogram. Bacteriophage typing of the strains revealed that all were untypable; this, in itself, was a good marker, because only 5 to 10% of S. typhimurium isolates in this country have this property. Agarose gel electrophoresis of isolates from the five patients revealed an identical plasmid banding pattern consisting of three large and three small plasmids. Highly resistant strains of S. typhimurium imported from the Far East may spread rapidly when introduced into a hospital nursery. Prompt institution of control measures may limit the outbreak and prevent systemic infections for which there are few effective therapeutic agents.