To evaluate the histopathologic findings in the eyes with retinoblastoma that had been treated only with chemoreduction. Clinicopathologic series. Study Material Ten eyes of 8 patients with retinoblastoma that were enucleated after therapy consisting only of systemic chemotherapy (chemoreduction). All cases received a chemoreduction regimen including a combination of intravenous carboplatin, etoposide phosphate, and vincristine sulfate. Adjuvant treatment to the tumor was not provided in any case. The enucleated globes were studied by routine light microscopy. Main Outcome Measure Histopathologic features of retinoblastoma following chemoreduction. At presentation, there were 8 eyes in Reese-Ellsworth group V, 1 eye in group IV, and 1 eye in group III. After chemoreduction (mean, 4 cycles; range, 1-6 cycles), the main tumor regressed a mean 34% in thickness and 24% in basal diameter. The indication for enucleation was retinoblastoma recurrence as subretinal and/or vitreous seeds in 7 eyes and extensive vitreous hemorrhage in 3 with uncertainty about viable-appearing tumor. In no case was enucleation performed for recurrence of the main tumor. In all eyes, there was histopathologic evidence of tumor regression. In 8 of 10 eyes, histopathologic examination disclosed tumor regression without viable-appearing retinoblastoma in the main tumor. Of these 8 eyes, 2 showed a completely calcified glial scar and 6 showed an apical calcified glial scar and a basal residual well-differentiated component with retinomalike and/or retinocytomalike features. In the remaining 2 eyes, an area of posttherapeutic regression was present but contained foci of mitotically active, viable-appearing malignant retinoblastoma cells. The 6 eyes found to contain well-differentiated component with retinomalike and/or retinocytomalike features showed a mean decrease of 17% in largest basal dimension and 32% in thickness after a mean of 3 cycles of chemoreduction. In contrast, the 4 eyes that did not contain well-differentiated component with retinomalike and/or retinocytomalike features showed a mean decrease of 35% in largest basal dimension and 55% in thickness after a mean of 5 cycles of chemoreduction. Of those 7 eyes enucleated for recurrent subretinal and/or vitreous seeds, viable tumor seeds were confirmed histopathologically in all cases. There was no histopathologic evidence of chemotherapeutic toxicity to the eye. Histopathologic examination of 10 enucleated eyes following chemoreduction alone revealed that the main retinoblastoma regressed in all eyes. Additionally 6 eyes showed basal residual well-differentiated component with retinomalike and/or retinocytomalike features, and these eyes also displayed less shrinkage with chemoreduction. Despite the lack of viable-appearing retinoblastoma within the main tumor, enucleation was performed for viable subretinal and/or vitreous seeds in 7 cases and confirmed histopathologically.