Intravitreal ocriplasmin was recently approved by the Food and Drug Administration to achieve medical vitreolysis in the setting of vitreomacular adhesion (VMA). We report a case of a 76-year-old woman who developed a lamellar macular hole following treatment with intravitreal ocriplasmin injection for VMA. A pathophysiological mechanism to explain this previously unreported complication of ocriplasmin injection is proposed.