OBJECTIVE A pilot study to evaluate the use of intravitreal methotrexate (MTX) for the treatment of uveitis and uveitic cystoid macular edema (CME). METHODS Prospective, consecutive, interventional case series. METHODS Fifteen eyes of 15 patients with a unilateral exacerbation of noninfectious intermediate, posterior uveitis, or panuveitis and/or CME such that visual acuity (VA) was 20/40 or worse, together with a history of increased intraocular pressure (IOP) in response to corticosteroid administration. METHODS Intravitreal injection of 400 microg in 0.1 ml MTX. METHODS The primary outcome measure was VA (using the Early Treatment Diabetic Retinopathy Study chart). Other outcome measures included ocular inflammation scores, time to relapse, levels of systemic corticosteroid and immunosuppressive therapy, and ocular coherence tomography. Potential complications of intravitreal MTX injection, including cataract progression, vitreous hemorrhage, retinal detachment, and corneal epitheliopathy, were assessed. RESULTS VA improved at all time points and was statistically significant at the 3- and 6-month follow-up examinations. The mean visual improvement was 4 lines at 3 months and 4.5 lines at 6 months, with no statistical difference between the best VA obtained after MTX injection and after previous corticosteroid treatment, including intravitreal triamcinolone acetate injection. Five patients relapsed after a median of 4 months; a similar improvement was seen after re-injection. Ocular inflammation scores improved at all time points, and systemic immunosuppressive medication was reduced in 3 of 7 patients taking this at the start of the trial. CONCLUSIONS In patients with uveitis and uveitic CME, intravitreal MTX can improve VA and reduce CME and, in some patients, allows the reduction of immunosuppressive therapy. Relapse occurs at a median of 4 months in some patients, but reinjection has similar efficacy.