In The Netherlands, retinoblastoma patients have been registered in the Utrecht national retinoblastoma registry since 1862. This register is virtually complete from 1945 onwards. We describe a unique epidemiological survey of the occurrence of non-ocular cancer in all patients registered during the period 1945-1970. The occurrence of non-ocular cancer in relatives of patients with hereditary retinoblastoma is also reported. One hundred and forty-one patients with hereditary retinoblastoma were studied for non-ocular second primary cancer. Nineteen patients died of retinoblastoma. The median follow-up of the surviving 122 patients was 25 years. Seventeen of these patients developed a second primary cancer, most frequently soft-tissue sarcoma. The cumulative incidence of non-ocular cancer was 19% at the age of 35, i.e., a 14-fold increase as compared to the general population. Twelve patients with hereditary retinoblastoma died of non-ocular cancer whereas none of 252 patients with non-hereditary retinoblastoma died of non-ocular cancer. Furthermore, among the parents of our hereditary retinoblastoma patients, 24 (born before 1945) had also been affected by retinoblastoma or had affected sibs. In the parents, 4 tumors occurred, of which 2 were rhabdomyosarcomas and 2 were urinary bladder cancers. Both types of non-ocular cancer were also encountered among the 122 patients with hereditary retinoblastoma. In 103 fathers and 103 mothers of patients with hereditary retinoblastoma who did not have retinoblastoma themselves, there was no previous family history of retinoblastoma. The fathers had a relative risk of 8.3 for pancreatic cancer compared to the general population. There was no significant increase in the number of non-ocular tumors in 332 sibs of patients with hereditary retinoblastoma.