Purpose Primary central nervous system lymphoma (PCNSL) is a non-Hodgkin lymphoma involving the brain with possible leptomeningeal and ocular involvement. This study aimed to evaluate the safety and efficacy of modified intravitreal injection regimen of methotrexate (MTX) for therapeutic management of vitreoretinal lymphoma. Materials and methods Forty human immunodeficiency virus (HIV)-negative Chinese patients with primary vitreoretinal lymphoma were included in this retrospective noncomparative interventional case series study. Patients were treated with a modified protocol of intravitreal injection of MTX (400 mu g/0.1 ml) according to the Intensive-Consolidation-Maintenance regimen. The Intensive phase of once-weekly intravitreal injections for 1 month, followed by the Consolidation phase of one injection every 2 weeks for 1 month, and then the Maintenance phase of once monthly for 1 month, for a total of 7 injections. The primary main outcome measures were clinical response to intravitreal chemotherapy, number of injections for clinical remission, progression-free survival (PFS), overall survival (OS), visual acuity (VA), complications during the study period, and cause of death were investigated. Results The duration of follow-up from the commencement of injection of MTX was 12-73 months (median 28, 30.55 +/- 14.73 months). A total of 61 eyes of 40 patients were cleared clinically from malignant cells after a median 6.57 +/- 3.12 (median 6, range 1-14) times of injection of MTX. A second remission was induced in 3 patients, who were treated with a further course of intravitreal chemotherapy after tumour recurred in their eyes. The median PFS and OS were 20.82 months (95% CI 14.64-27.01) and 29.29 months (95% CI 16.16-42.41), respectively. Complications that occurred during the period of treatment and follow-up included corneal epitheliopathy (3 of 61 eyes) and cataract (6 of 61 eyes). There were no cases of maculopathy, vitreous haemorrhage, optic atrophy, and sterile endophthalmitis. No patient had an irreversible loss of vision that could be attributed to the intravitreal injection of MTX. Conclusions It can be concluded that the modified intravitreal injection regimen of MTX is an effective therapeutic approach in inducing clinical remission of intraocular involvement in PCNSL patients, associated with few complications. However, further study needs to be conducted to indicate whether the proposed approach extends life expectancy.