Patients with recurrent episodes of Escherichia coli bloodstream infection (REC-BSI) have been described previously only in small studies. We report on the incidence, clinical significance, and predisposing conditions of REC-BSI in a general hospital from 1992 to 2005. All patients with E. coli bloodstream infection (EC-BSI) were retrieved from our database. We defined recurrent episodes as those occurring at least 1 month apart after a clinical response (cases). To study risk factors for REC-BSI, we randomly selected a third of the REC-BSI cases and a similar number of controls (patients with a single EC-BSI). Available E. coli isolates from initial and recurrent episodes were typed using repetitive-extragenic-palindromic-sequences to distinguish between relapse and reinfection. During the study period there were 4287 episodes of EC-BSI in 3970 patients; of these, 251 (6.3%) patients had 568 episodes of recurrence (13.3%). We selected 81 cases and 81 controls for study. The underlying conditions of patients with REC-BSI included immunosuppression (33%), urinary (24%) or biliary obstruction (16%), chronic liver disease (16%), presence of a central venous catheter (8%), and miscellaneous entities (3%). Male sex, presence of hematologic malignancy, inadequate antibiotic treatment, and an extraurinary source of the BSI were independent risk factors for recurrence in the multivariate analysis. Molecular typing performed in 88 infections from 44 patients showed that 47% of REC-BSI were relapses rather than reinfections. Recurrence of E. coli BSI is not an uncommon phenomenon and includes relapses (47%) and reinfections (53%). Recurrence should suggest not only the presence of urinary or biliary obstruction, but also the presence of immunosuppression.