The authors describe two children who presented with atypical posterior uveitis and who were subsequently diagnosed as having diffuse infiltrating retinoblastoma. A review of these two cases and 26 previously published cases was performed to assess the epidemiology, presenting signs, and usefulness of diagnostic tests. In contrast to typical retinoblastoma, results of histologic analysis showed that only 4 of the 28 cases with infiltrating lesions contained calcium. Computed tomography scans and ultrasonography were not particularly helpful and many eyes required an anterior chamber paracentesis to establish the correct diagnosis. A systematic approach to the diagnosis of diffuse infiltrating retinoblastoma is presented.