Background: Because of the increasing development of antimicrobial resistance, there is a greater responsibility within the medical community to limit the exposure of patients to antibiotics. We tested the hypothesis that shorter courses of antibiotics are associated with similar or better results than longer durations. We also sought to investigate the difference between a fixed duration of therapy and one based on physiologic measures such as fever and leukocytosis. Methods: All infectious episodes on the general surgery units of the University of Virginia Health System from December 15, 1996, to July 31, 2003, were analyzed retrospectively for the relation between the duration of antibiotic therapy and infectious complications (recurrent infection with the same organism or at the same site). All infections associated with either fever or leukocytosis were categorized into quartiles on the basis of the absolute length of antibiotic administration or the duration of treatment following resolution of fever or leukocytosis. Multivariate logistic regression models were developed to estimate the independent risk of recurrence associated with a longer duration of antibiotic use. Results: Of the 5,561 treated infections, 4,470 were associated with fever (temperature ≥38°C) or leukocytosis (white blood cell count ≥11,000/mm3). For all infections, whether analyzed by absolute duration or time from resolution of leukocytosis or fever, the first or second quartiles (0-12 days, 0-9 days, 0-9 days, respectively) were associated with the lowest recurrence rates (14-18%, 17-23%, 18-19%, respectively). Individual analysis of intra-abdominal infections and pneumonia yielded similar results. The fixed-duration groups received fewer days of antibiotics on average, with outcomes similar to those in the physiologic parameters group. Conclusions: Shorter courses of antibiotics were associated with similar or fewer complications than prolonged therapy. In general, adopting a strategy of a fixed duration of therapy, rather than basing duration on resolution of fever or leukocytosis, appeared to yield similar outcomes with less antibiotic use.