BACKGROUND: High-mobility group proteins A (HMGA) are more abundant in rapidly dividing and transformed cells. These are a group of proteins regulating tumorigenesis and tumor invasion. Increased expression of HMGA1 and HMGA2 has been reported in various benign and malignant tumors. The aim of the present study was to analyze expression of HMGA1 and HMGA2 proteins in retinoblastoma. METHODS: Protein expression of HMGA1 and HMGA2 in 80 formalin-fixed retinoblastoma tissues was performed by immunohistochemistry, and their mRNA expressions were analyzed on 40 fresh primary enucleated retinoblastoma samples by semiquantitative reverse transcription polymerase chain reaction. Results were then correlated with clinicopathologic parameters. RESULTS: Immunohistochemical analysis of HMGA1 and HMGA2 was seen in 56.25% and 58.75% of retinoblastoma cases, respectively. mRNA expressions of HMGA1 and HMGA2 was found to be 57.55% and 62.5%, respectively. The mRNA results correlated well with immunostaining results. Expression of both HMGA1 and HMGA2 was significantly associated with choroidal invasion and poor tumor differentiation. CONCLUSIONS: HMGA1 and HMGA2 proteins may contribute to tumorigenesis of Rb. Expression of HMGA1 and HMGA2 predicts poor prognosis and could serve as a therapeutic target in the management of RB. Further experiments are needed to determine the role of these proteins as therapeutic targets in tumorigenesis.