In this retrospective observational cohort study, we aimed to describe the rate of extracorporeal membrane oxygenation (ECMO) circuit change, the associated risk factors and its relationship with patient characteristics and outcome in patients receiving venovenous (VV) ECMO at our center between January 2015 and November 2017. Twenty-seven percent of the patients receiving VV ECMO (n = 224) had at least one circuit change, which was associated with lower ICU survival (68% vs 82% p=0.032) and longer ICU stay (30 vs. 17 days p < 0.001). Circuit duration was similar when stratified by gender, clinical severity, or prior circuit change. Hematological abnormalities and increased transmembrane lung pressure (TMLP) were the most frequent indication for circuit change. The change in transmembrane lung resistance (Δ TMLR) gave better prediction of circuit change than TMLP, TMLR, or ΔTMLP. Low postoxygenator PO₂ was indicated as a reason for one-third of the circuit changes. However, the ECMO oxygen transfer was significantly higher in cases of circuit change with documented “low postoxygenator PO₂” than those without (244 ± 62 vs. 200 ± 57 ml/min; p = 0.009). The results suggest that circuit change in VV ECMO is associated with worse outcomes, that the Δ TMLR is a better predictor of circuit change than TMLP, and that the postoxygenator PO₂ is an unreliable proxy for the oxygenator function.