Purpose Initial response of intraocular retinoblastoma to chemotherapy has encouraged primary chemotherapy instead of primary enucleation for eyes with clinical features suggesting high risk of extraocular extension or metastasis. Upfront enucleation of such high-risk eyes allows pathologic evaluation of extraocular extension, key to management with appropriate surveillance and adjuvant therapy. Does chemotherapy before enucleation mask histologic features of extraocular extension, potentially endangering the child's life by subsequent undertreatment? Methods We performed retrospective analysis of 100 eyes with advanced retinoblastoma enucleated with, or without, primary chemotherapy, in Beijing Tongren Hospital, retrospectively, from October 31, 2008. The extent of retinoblastoma invasion into optic nerve, uvea, and anterior chamber on histopathology was staged by pTNM classification. The treatment groups were compared for pathologic stage (Cochran-Armitage trend test) and disease-specific mortality (competing risks methods). Results Children who received chemotherapy before enucleation had lower pTNM stage than primarily enucleated children (P = .01). Five patients who received pre-enucleation chemotherapy died as a result of extension into brain or metastasis. No patients who had primary enucleation died. For children with group E eyes, disease-specific survival (DSS) was lower with pre-enucleation chemotherapy (n = 45) than with primary enucleation (n = 37; P = .01). Enucleation longer than 3 months after diagnosis was also associated with lower DSS (P < .001). Conclusion Chemotherapy before enucleation of group E eyes with advanced retinoblastoma downstaged pathologic evidence of extraocular extension, and increased the risk of metastatic death from reduced surveillance and inappropriate management of high-risk disease, if enucleation was performed longer than 3 months after diagnosis. J Clin Oncol 29:845-851. (C) 2011 by American Society of Clinical Oncology