Purpose We report a case of acute bilateral Descemet membrane endothelial keratoplasty (DMEK) rejection two weeks following BNT162b2 mRNA COVID-19 vaccine (Pfizer-BioNTech), reflecting on possible changes to the management of patients with DMEK scheduled for COVID-19 vaccination. Patients and Methods A 94-year-old woman with Fuchs’ endothelial dystrophy who underwent DMEK 24 months earlier (right eye) and 20 months earlier (left eye) demonstrated bilateral graft rejection two weeks after the first dose of COVID-19 vaccine. Standard treatment regimen was followed, and clinical status documented with slit-lamp examination and swept-source optical coherence tomography throughout. Results Preoperative best corrected visual acuity (BCVA) and corneal thickness (CT) were 0.3 and 679µm right eye and 0.2 and 668µm left eye. Postoperative BCVA and CT were 0.7 and 559µm right eye and 0.4 and 590µm left eye. Standard treatment regimen consisted of dexamethasone/tobramycin and ketorolac, four times daily. At one month, both preparations were discontinued, replaced by dexamethasone 0.1% four times daily. At three months, this was tapered to once daily. Post-rejection, BCVA and CT were 0.2 and 710µm right eye and 0.3 and 710µm left eye. Treatment was with dexamethasone/tobramycin six times daily. Poor response resulted in re-DMEK transplantation, starting in the left eye. At one-month follow-up, BCVA and CT were 0.5 and 538µm right eye and 0.63 and 504µm left eye. Conclusion We report the first acute bilateral DMEK graft rejection after a single dose of COVID-19 vaccine. We recommend clinicians exercise vigilance and consider dexamethasone 0.1% during the vaccination period.