Blood stream infection (BSI) is a potentially lethal complication in patients receiving extracorporeal membrane oxygenation (ECMO). It may be particularly common in patients with veno-venous ECMO due to their long hospitalization in the intensive care unit. Given that these patients have concurrent indwelling central venous catheters (CVC), it is unclear whether the ECMO circuit, CVC, or both, contribute to BSI. This study evaluated the risk factors associated with BSI in patients receiving veno-venous ECMO in a single institution study of 61 patients from 2016 through 2019. All ECMO catheters and the circuit oxygenator fluid were aseptically collected and analyzed for microorganisms at the time of decannulation. New BSI was diagnosed in 15 (24.6%) patients and increased mortality by threefold. None of the ECMO catheters or oxygenator fluid were culture positive. BSI increased with CVC use of over 8 days and was significantly lowered when CVC were exchanged by day 8 compared with patients with exchanges at later points (15.0% vs. 42.8%, p = 0.02). Median length of CVC use in the BSI-negative and BSI-positive group were 6.3 ± 5.0 and 9.4 ± 5.1, respectively (p = 0.04). In summary, BSI is a potentially lethal complication in patients receiving ECMO. Indwelling CVC, not the ECMO circuitry, is the likely contributor for BSI, and exchanging CVC by day 8 can reduce the incidence of BSI.