Two gross intragenic deletions of the retinoblastoma (RB) gene from patients with sporadic hereditary disease were analysed in detail. This study was undertaken to determine whether there were common mechanisms for these deletions and whether changes found in the tumors were identical to those found in the constitutional cells. Short repeats at the deletion breakpoints were found in both tumors, one resulting in a 2.0 kb deletion including exons 21 and 22, and the other producing a 3.7 kb deletion including exons 14-17. In addition, the identical sequence changes documented in genomic DNAs and transcripts of these tumors were also observed in the constitutional cells. Both deletions were in-frame and resulted in a truncated transcript and protein identical to the expected size based on the exons deleted. These studies provide further documentation of the events which represent the actual 'two hits' originally hypothesized to be responsible for retinoblastoma development.