Introduction: Prolonged invasive mechanical ventilation (IMV) after lung transplantation is an appealing early prognostic outcome as it can be reproducibly assessed both prospectively and retrospectively. Whether use of IMV at 72 h after lung transplantation is associated with post-transplant graft survival is unknown. Methods: We performed a retrospective cohort study of 1511 participants in the multi-center Lung Transplant Outcomes Group cohort (2011–2018). Using Cox proportional hazards models and restricted mean survival time, we investigated whether IMV at 72 h was associated with post-transplant graft survival. We secondarily evaluated whether IMV at 72 h was concordant with severe primary graft dysfunction (PGD). Results: Participants requiring IMV at 72 h after transplant were sicker at transplantation (higher lung allocation score [LAS], increased extracorporeal membrane oxygenation, or IMV bridge) and more likely to have severe PGD. Use of IMV at 72 h was associated with 55% (95% CI 26%–92%) increased hazards of death or re-transplantation after adjustment for age, ECMO, diagnosis, LAS, and intra-operative transfusion. The association between IMV and graft survival was modified by severe PGD (p-for interaction 0.002) but not by pre-transplant ECMO (p-for interaction 0.88) or pre-transplant IMV (p-for interaction 0.92). IMV was associated with increased risk of death or re-transplantation among those with PGD (HR 2.35, 95% CI 1.43–3.85) but not among those without PGD (HR 1.04, 95% CI 0.77-1.41). Conclusion: Requirement of IMV at 72 h is an important early post-transplant outcome associated with post-transplant survival. This appears driven by those with severe PGD.