AIMS: To compare the effect of three-drug regimen (melphalan, topotecan and carboplatin) with two-drug regimen (melphalan and topotecan) on the globe salvage outcomes of retinoblastoma (Rb) with intra-arterial chemotherapy (IAC). METHODS: This study included 83 patients with 87 eyes received two-drug regimen IAC, and 95 patients with 97 eyes received three-drug regimen IAC. Propensity score matching was applied, and 84 matched (42:42) patients (eyes) were analysed. All Rb patients underwent an ophthalmologic examination before IAC using a wide-angle digital fundus camera, which was repeated monthly after the globe salvage management. Progression-free ocular survival (PFOS), relapse rate and local complications were analysed per affected eye. Analysis of overall survival (OS) and systemic complications was based on Rb individuals. RESULTS: Eyes treated with three-drug regimen IAC presented with higher overall PFOS than those treated with two-drug regimen IAC (p=0.026). Stratified analysis showed PFOS rate in three-drug group was higher than two-drug group among group D eyes (88.5% vs 60.6%, p=0.009). Consistently, among group E eyes, three-drug group correlated with a better PFOS, compared with two-drug group (42.9% vs 23.5%, p=0.002). There did not present with significant differences in OS (p=0.853), relapse rate (p=0.291), incidence of moderate-severe myelosuppression (grade 3-4, p=0.564) or ophthalmic artery obstruction (p=0.998) between these two groups. CONCLUSIONS: Three-drug regimen was a superior IAC management compared with two-drug regiment, with improved progression-free ocular outcome for eyes of advanced retinoblastomas.