Background: An increasing number of patients with intestinal failure are receiving home parenteral nutrition (HPN). Associated complications include bloodstream infections (BSIs), but data on rates and risk factors for HPN‐related BSIs are scarce. Methods: A retrospective review was conducted of patients enrolled in the regional HPN program between 2001 and 2008. Demographic information and data on indication for HPN, duration of PN therapy, type and date of insertion of central venous access device, and blood culture results were recorded. Results: In total, 155 patients (165 courses of HPN) were included for a total of 45,876 catheter days. The mean patient age was 49 years, and 105 (64%) patients were female. A total of 105 organisms were cultured from 93 distinct episodes of BSIs. The rate of BSI was found to be 2.0 per 1000 catheter days, but excluding BSIs with a single positive culture of coagulase‐negative staphylococcus and diphtheroid bacilli, the rate of infection was 1.4 per 1000 catheter days. Male sex and underlying malignancy were significant predictors of BSI, with hazard ratios of 1.69 (95% confidence interval [CI], 1.14–2.60; P = .009) and 2.38 (95% CI, 1.53–3.50; P < .001). Conclusion: In a large heterogeneous group of HPN patients, the BSI rate ranged between 1.4 and 2.0 infections per 1000 catheter days. Isolated organisms were similar to those found in hospitalized patients. Male sex and underlying malignancy were significant risk factors for BSI. These high‐risk patients are likely to benefit from interventions aimed at reducing BSIs.