Abstract Purpose: The purpose of this study was to determine the efficacy of an intraoperative intravitreal pegaptanib injection during phacoemulsification in preventing the development of pseudophakic cystoid macular edema (CME) following cataract surgery. Methods: This prospective, controlled pilot study was carried out at the Department of Ophthalmology, Nuevo Hospital Universitario y Politécnico La Fe, Valencia (Spain). Five hundred patients with cataract and healthy retina were included in the study. Patients were assigned in a 1:1 ratio to receive an intraoperative intravitreal pegaptanib injection ( n =250) or not (control group, n =250) associated with standardized phacoemulsification surgery and postoperative treatment. Any surgical complication was considered as an exclusion criterion. The main outcome measure was the incidence of CME at 4 weeks postsurgery, defined as a central foveal thickness greater than 350 μm as measured by spectral-domain optical coherence tomography with associated cystoid changes. Results: The incidence of CME by the fourth postoperative week was 0.4% ( n =1) in the pegaptanib group and 4.4% ( n =11) in the control group ( P =0.009). Conclusions: Prophylactic use of intravitreal pegaptanib immediately after phacoemulsification was effective in preventing CME by the fourth postoperative week. The inclusion of intravitreal pegaptanib injection in the prophylaxis of pseudophakic CME will be considered for complicated cases in forthcoming studies.