Purpose: To highlight the efficacy and safety of a combined surgical and medical therapy (with intraocular and systemic methotrexate [MTX]) of pediatric rhegmatogenous retinal detachments (RRDs) complicated by proliferative vitreoretinopathy (PVR). Methods: Three pediatric patients with RRD complicated by PVR in the setting of underlying atopic dermatitis and/or uveitis were treated with a combination of vitreoretinal surgery and intraoperative intravitreal MTX (40 mg) infusion followed by at least 1 injection of 200 μg of MTX into the silicone oil–filled vitreous cavity. The patients received short-term systemic immunosuppression with systemic (oral or subcutaneous 20 mg weekly MTX for 12 weeks) and/or steroids. Results: Retinal reattachment with visual acuity improvement was achieved in all eyes following a single surgery and remained to the final follow-up after oil removal. No side effects of intraocular or systemic MTX were observed. Conclusions: This combination therapy could be a successful strategy for treating pediatric patients with RRD with or without PVR.