AIM:To report a case of diffuse infiltrating retinoblastoma that proved to be diagnostic challenge because of its atypical presentation. METHODS:We described a 10 years old boy presented with cataract and features of ocular inflammation post-operatively, and was finally diagnosed as diffuse infiltrating retinoblastoma.RESULTS:The masquerading features, diagnostic approach, surgical management and histopathology findings were presented. In this case, cytology study of aqueous humor cells confirmed the diagnosis while radioimaging demonstrated a limited diagnostic value.CONCLUSION:The case highlights the diagnostic challenge of diffuse infiltrating retinoblastoma. Ophthalmologist should be aware of the atypical presentation of diffuse infiltrating retinoblastoma and must be vigilant in managing similar cases.