To study temporal changes in the antibiotic resistance of Salmonella in the United States, a study design similar to that of a 1967 study was used to determine the antibiotic sensitivity of 754 human nontyphoid Salmonella isolates sent to the Center for Disease Control, Atlanta, Georgia, in 1975. The frequency of resistance to one or more of the same nine antibiotics used in both studies increased significantly during the eight years in Salmonella typhimurium (40%-59%; P = 0.004), other serotypes (14%-23%; P = 0.001), and all serotypes combined (21%-31%; P < 0.001). The increase in frequency of resistance was significant for streptomycin (P = 0.022), sulfonamides (P < 0.001), ampicillin (P < 0.001), and kanamycin (P < 0.001). No chloramphenicol-resistant isolates were found in the 1967 study, whereas six isolates (0.8%) were resistant in 1975. The frequency of strains resistant to six or more antibiotics increased greatly (0.8%-5.0%; P < 0.001). These data document a continuing increase in antimicrobial resistance among Salmonella isolates.