A case-control study was performed using the records of patients hospitalized for typhoid fever at Dicle University Hospital, Diyarbakir, Turkey, between 1994 and 1998. Case patients with enteric perforation were compared with control patients with typhoid fever but no enteric perforation. Risk factors for perforation were determined using logistic regression modeling. Forty case patients who had surgery because of typhoid enteric perforation were compared with 80 control patients. In univariate analyses, male sex (p = 0.01), age (p = 0.01), leukopenia (p = 0.01), inadequate antimicrobial therapy prior to admission (p = 0.01), and short duration of symptoms (p = 0.01) were significantly associated with perforation. In multivariate analysis, male sex (odds ratio (OR) = 4.39, 95% confidence interval (CI): 1.37, 14.09; p = 0.01), leukopenia (OR = 3.88, 95% CI: 1.46, 10.33; p = 0.04), inadequate treatment prior to admission (OR = 4.58, 95% CI: 1.14, 18.35; p = 0.03), and short duration of symptoms (OR = 1.22, 95% CI: 1.10, 1.35; p = 0.001) were significant predictors of perforation. A short duration of symptoms, inadequate antimicrobial therapy, male sex, and leukopenia are independent risk factors for enteric perforation in patients with typhoid fever.