Purpose The aim was to evaluate the impact of protocol changes in selective ophthalmic arterial infusion (SOAI) for treatment of retinoblastoma (Rb). Methods A retrospective review was completed of 35 patients with Rb who were treated with SOAI between March 2010 and January 2017. Treatment details were tabulated for each SOAI session. SOAI protocol was changed in June 2015, and differences before and after this change were evaluated using two-tail chi-square tests and independent sample t-tests to note any differences in technical complications, need for enucleation, and other outcome variables Results 125 SOAI sessions occurred. No technical complications occurred during the study. Two complications (1.6%) occurred in the postoperative setting. Both complications occurred prior to the change in protocol. Comparing the complication rates between the two protocols showed no significant difference (2.2% versus 0.0%; p = 0.505); 29 of 43 (67.4%) eyes had their vision preserved overall. Conclusions SOAI is an effective treatment for Rb. The refined protocol described herein was associated with fewer complications.