The administration per os of a single large dose (50 mg) of streptomycin to 9 to 12-week-old female CF-1 mice was followed by a marked increase in susceptibility to infection with a streptomycin-resistant strain of Salmonella enteyitidis inoculated by the same route. Fewer than 10 microorganisms sufficed to infect half the streptomycin-treated mice, whereas approximate, 10⁶ were required to infect half the untreated controls. The effect of smaller doses of streptomycin was less pronounced. Infection was determined by recovery of the test microorganism from feces on the 6th day after inoculation and/or from spleen during the 2nd or 3rd week. In control mice, small inocula of S. enteritidis passed through the gastrointestinal tract without multiplying and were excreted in the feces within 24 hours. In streptomycin-treated mice, similar inocula were able to multiply rapidly in the large intestine during the 24-hour period. The effect of streptomycin did not persist. It diminished gradually as the interval between treatment and inoculation lengthened but was still demonstrable on the 5th day. It was lost more rapidly among mice housed in groups than in mice isolated in individual cages. The loss was still more rapid when the group included a normal, untreated mouse which contaminated the cage with its fecal microflora. Prolonged administration of streptomycin in drinking water increased susceptibility little, if any, more than the equivalent of 1 day's intake administered as a single dose. Mice given 50 mg of streptomycin per os showed no evidence of any toxic effect either by their outward appearance or by gross or microscopic examination of the gastrointestinal tract. S. enteritidis infection initiated by parenteral inoculation, either intraperitoneally or subcutaneously, was not affected by streptomycin administered per os, nor was the bacterial population in the subcutaneous infection increased by injection of streptomycin directly into the site of inoculation. Administration of streptomycin per os increased susceptibility to enteric infection with a strain of staphylococcus which was unable to establish itself in the gut of untreated mice. Penicillin in sufficient dosage per os increased susceptibility to infection with S. enteritidis almost as effectively as streptomycin. The enhanced susceptibility of the mouse's intestinal tract is believed to be due solely to the change in the ecology of the enteric microflora resulting from the antimicrobial action of streptomycin (or penicillin) within the lumen of the gut.