To assess factors associated with antimicrobial-resistant Salmonella infections and trends in resistance, a prospective study of patients with culture-confirmed salmonellosis was done in 1989-1990. Patients with resistant infections were more likely than those with susceptible infections to be hospitalized (P = .006), to be < 1 year old (P = .003), to be black (P = .013), and to have recently been treated with an antimicrobial agent (P = .085). Compared with data from a similar study in 1979-1980, increases were seen in the percentage of patients with resistant infections (from 17% to 31%), in the resistance to ampicillin (10% to 14%), and in the frequency of isolates found in blood (1% to 11%). These data show that treatment of Salmonella infections may be complicated by growing resistance to clinically important antimicrobial agents and by an increasing frequency of extraintestinal complications. Antimicrobial agents with little demonstrated resistance should be considered for patients with complicated illness and at high risk of having a resistant infection.