Cannulation-related complications are a known source of morbidity in patients supported on veno-arterial extracorporeal membrane oxygenation (VA-ECMO). Despite its prevalence, little is known regarding the outcomes of patients who suffer such complications. This is a single institution review of cannulation-related complications and its effect on mortality in patients supported on VA-ECMO from January 2010–2015 using three cannulation strategies: axillary, femoral, and central. Complications were defined as advanced if they required major interventions (fasciotomy, amputation, site conversion). Patients were divided into two groups (complication present vs. not present) and Kaplan-Meier analysis was performed to determine any differences in their survival distributions. There were 103 patients supported on VA-ECMO: 41 (40%), 36 (35%), and 26 (25%) were cannulated via axillary, femoral, and central access, respectively. Cannulation-related complications occurred in 33 (32%) patients and this did not differ significantly between either axillary (34%), femoral (36%), or central (23%) strategies (P = 0.52). The most common complications encountered were hemorrhage and limb ischemia in 19 (18%) and 11 (11%) patients. Hemorrhagic complications did not differ between groups (P = 0.37), while limb ischemia and hyperperfusion were significantly associated with femoral and axillary cannulation, at a rate of 25% (P < 0.01) and 15% (P = 0.01), respectively. There was no difference in the incidence of advanced complications between cannulation groups: axillary (12%) vs. femoral (14%) vs. central (8%; P = 0.75). In addition, no increase in mortality was noted in patients who developed a cannulation-related complication by Kaplan-Meier estimates (P = 0.37). Cannulation-related complications affect a significant proportion of patients supported on VA-ECMO but do not differ in incidence between different cannulation strategies and do not affect patient mortality. Improved efforts at preventing these complications need to be developed to avoid the additional morbidity in an already critical patient population.