Abstract Aim To assess the efficacy and safety of intravitreal methotrexate (MTX) infusion (IMI) during pars plana vitrectomy (PPV) in patients with rhegmatogenous retinal detachment (RRD) to prevent proliferative vitreoretinopathy (PVR) in patients with established PVR grade C and patients at high risk for PVR development. Settings and Design A prospective comparative interventional study conducted from September 2020 till November 2021 at Ain Shams University Hospitals, Egypt. Materials and Methods Forty-seven eyes of patients with RRD undergoing PPV were divided into case group receiving IMI during the surgery and control group. Each group was subdivided into a subgroup with high-risk patients to develop PVR and a subgroup with established PVR grade C preoperatively. Outcome measures at the end of three months postoperatively were retinal attachment rate, incidence of PVR, reoperation rate to flatten the retina and the changes in retina and/or optic nerve function assessed by full field electroretinogram (ff-ERG) and flash visually evoked potential (VEP) Results Seven cases (15%) and four cases (9%) developed PVR after one month and three months respectively. Five cases (10 %) required reoperation to re-flatten the retina, 43 cases (91 %) had complete flattening of the retina after three months. No statistically significant differences were reported between the studied groups regarding the studied outcome measures, and no serious adverse events were reported secondary to IMI. Conclusion IMI use was found to be safe in intraocular use, but it did not affect the anatomical success rate. Key words: Proliferative Vitreoretinopathy, Recurrent Retinal Detachment, Electrophysiology. Key Messages: More studies need to be conducted to further evaluate if MTX has a role in the prevention of PVR after vitrectomy.