Background. Major bleeding has been a common and serious complication with poor outcomes in ECMO patients. With a novel, less-invasive cannulation approach and closer coagulation monitoring regime, the incidence of major bleeding is currently not determined yet. Our study aims to examine the incidence of major bleeding, its determinants, and association with mortality in peripheral-ECMO patients. Method. We conducted a single-center retrospective study on adult patients undergoing peripheral-ECMO between January 2019 and January 2020 at a tertiary referral hospital. Determinants of major bleeding were defined by logistic regression analysis. Risk factors of in-hospital mortality were determined by Cox proportional hazard regression analysis. Results. Major bleeding was reported in 33/105 patients (31.4%) and was associated with higher in-hospital mortality [adjusted hazard ratio (aHR) 3.56, 95% confidence interval (CI) 1.63–7.80,
p
<
0.001
). There were no significant difference in age, sex, ECMO indications, ECMO modality, pre-ECMO APACHE-II and SOFA scores between two groups with and without major bleeding. Only APTT >72 seconds [adjusted odds ratio (aOR) 7.10, 95% CI 2.60–19.50,
p
<
0.001
], fibrinogen <2 g/L [aOR = 7.10, 95% CI 2.60–19.50,
p
<
0.001
], and ACT >220 seconds [aOR = 3.9, 95% CI 1.20–11.80,
p
=
0.017
] on days with major bleeding were independent predictors. Conclusions. In summary, major bleeding still had a fairly high incidence and poor outcome in peripheral-ECMO patients. APTT > 72 seconds, fibrinogen < 2 g/L were the strongest predicting factors for major bleeding events.