Background The use of post-enucleation adjuvant therapy to decrease the extraocular relapse rate is frequently considered, but there is much controversy about the indications for adjuvant therapy. The aim of this retrospective study was to observe the treatment and prognosis for different degrees of invasion of eye tissue in retinoblastoma (RB) and identify the indications for post-enucleation adjuvant therapy. Methods We recruited 537 children who had been diagnosed with unilateral RB and had received enucleation from January 2006 to December 2012 in our hospital, and divided them into three groups according to their number of histopathologic risk factors: 0 factor, 1 factor, or >= 2 factors. Histopathologic high-risk factors included invasion of the optic nerve posterior to the ethmoid plate (including optic nerve stumps) and extensive invasions of the choroid, sclera, anterior chamber, iris, and ciliary body. Treatment was delivered accordingly, and the prognosis of different degrees of histopathologic invasion was observed. The subjects were followed up for 6 months to 7 years (average follow-up time: 35 months). Statistical analysis was analyzed using X-2 test. P<0.05 was considered significant. Results Of the 537 RB patients who received enucleation, 25 died (overall survival: 95.3%). Of the 369 (68.7%) with no histopathologic risk factors, 1 died of recurrence, with a mortality rate of 0.3%, whereas of the 168 (31.3%) with histopathologic risk factors, 26 had recurrences and 24 died (mortality rate: 14.3%; P=0.000). Of the 93 patients (17.3%), each of whom had a single risk factor, nine had recurrences, 16 died (8.6%). Of the 75 patients (14%) with two or more high-risk factors, 16 died (21.3%). These differences were statistically significant between the three (P=0.000). Conclusion Chemotherapy is recommended for patients with histopathologic risk factors, especially those with two or more histopathologic risk factors.