We report a case of possible venous air embolism (VAE) during trans pars plana vitrectomy with air-fluid exchange of the vitreous cavity. Shortly after initiation of air-fluid exchange, decreases in end-tidal CO2, oxygen saturation, and blood pressure were observed. The patient rapidly progressed to cardiac arrest unresponsive to cardiopulmonary resuscitation, and recovered after the application of percutaneous cardiopulmonary support. Prompt termination of air infusion is needed when VAE is suspected during air-fluid exchange, and extracorporeal life support should be considered in fatal cases. Although the incidence is rare the possibility of VAE during ophthalmic surgery clearly exists, and therefore awareness and vigilant monitoring seem critical.