Data for 26 cases of nonradiogenic osteosarcomas that developed in patients with retinoblastoma and in their close relatives were collected from the literature and analyzed. The distribution of unaffected and unilaterally and bilaterally affected cases of retinoblastoma agreed with the expectation that risk to osteosarcoma did not differ by the phenotypes of the gene carriers. This finding indicated not only that increased risk to second primary tumors was a pleiotropic effect of the retinoblastoma gene but also that host resistance to the gene effects was tissue-specific. The risk of gene carriers to nonradiogenic osteosarcoma was estimated at 1.2%, and the relative risk was estimated at 230. Liability of the gene carriers to osteosarcoma could be regarded as a multifactorial threshold character, and heritability was estimated at 71 %. Results of analyses of ages at diagnosis suggested that nonradiogenic osteosarcoma developed slightly earlier in carriers of the retinoblastoma gene than in children not carrying the gene. These findings are discussed in the light of the host resistance model in which genes involved in tissue resistance must be suppressors to an error in differentiation (presumably a crucial event in malignant transformation) and radiogenic osteosarcoma in gene carriers is ascribed to the accumulation of induced mutations in that suppressor system