Extracorporeal membrane oxygenation (ECMO), a rescue therapy for pulmonary failure, has traditionally been limited by anticoagulation requirements. Recent practice has challenged the absolute need for anticoagulation, expanding the role of ECMO to patients with higher bleeding risk. We hypothesize that mortality, bleeding, thrombotic events, and transfusions do not differ between heparin-sparing and full therapeutic anticoagulation strategies in veno-venous (VV) ECMO management. Adult VV ECMO patients between October 2011 and May 2018 at a single center were reviewed. A heparin-sparing strategy was implemented in October 2014; we compared outcomes in an as-treated fashion. The primary end point was survival. Secondary end points included bleeding, thrombotic complications, and transfusion requirements. Forty VV ECMO patients were included: 17 (147 circuit-days) before and 23 (214 circuit-days) after implementation of a heparin-sparing protocol. Patients treated with heparin-sparing anticoagulation had a lower body mass index (28.5 ± 7.1 versus 38.1 ± 12.4, P = 0.01), more often required inotropic support before ECMO (82 versus 50%, P = 0.05), and had a lower mean activated clotting time (167 ± 15 versus 189 ± 15 s, P < 0.01). There were no significant differences in survival to decannulation (59 versus 83%, P = 0.16) or discharge (50 versus 72%, P = 0.20), bleeding (32 versus 33%, P = 1.0), thromboembolic events (18 versus 39%, P = 0.17), or transfusion requirements (median 1.1 versus 0.9 unit per circuit-day, P = 0.48). Survival, bleeding, thrombotic complications, and transfusion requirements did not differ between heparin-sparing and full therapeutic heparin strategies for management of VV ECMO. VV ECMO can be a safe option in patients with traditional contraindications to anticoagulation.