During 1972 a large epidemic, in excess of 10,000 cases, of typhoid fever occurred in Mexico City, Pachuca, and other communities of Mexico. The main characteristic of the epidemic, in addition to the large number of persons affected, was the prevalence of a strain of Salmonella typhi which was highly resistant to chloramphenicol both in vivo and in vitro, and which belonged to a single phage type, Vi degraded approaching type A. Of 493 strains of S. typhi studied during the outbreak, 452 (91.7%) were resistant to chloramphenicol (CM), tetracycline (TC), streptomycin (SM), and sulfonamides (SU). The epidemic strain owes its resistance to an R factor which is easily transferable to Escherichia coli K-12 and which appears to be stable. In the third month of the outbreak, a strain of S. typhi resistant to CM, TC, SM, SU, ampicillin (AM), and kanamycin (KM) was isolated from a patient with severe typhoid fever. During the following 9 months, six additional strains of S. typhi resistant to AM, CM, TC, SM, and SU were also isolated. Transfer experiments to E. coli K-12 indicate that these strains are infected with two different R factors, one causing CM, TC, SM, and SU resistance and the other causing AM or AM and KM resistance. The frequency of transfer of the resistance in overnight crosses was in the order of 10−4 for CM, TC, SM, and SU and 10−6 for AM or AM, and KM. The appearance of these strains resistant both to chloramphenicol and ampicillin was a cause for concern for the clinicians; fortunately, they have remained an infrequent cause of disease.