One hundred thirty-five patients younger than 30 years with osteosarcoma were treated at the Chiba Cancer Center between 1976 and 1999. They included six patients with second cancer after cure of osteosarcoma (group A) and three patients with osteosarcoma as second cancer after cure of childhood cancers (group B). Third cancer occurred in one patient of group A. The clinical features of these nine patients were studied. The diagnoses of second cancer in group A consisted of two acute myelogenous leukemias, two breast carcinomas, one malignant phyllodes tumor of breast, and one ovarian carcinoma. The third cancer was uterine leiomyosarcoma. Second cancer occurred an average of 7.2 years after occurrence of osteosarcoma. The diagnoses of first cancer in group B consisted of one adrenocortical carcinoma, one malignant teratoma of sacrum, and one ovarian carcinoma (yolk sac tumor). Osteosarcoma occurred on average 12.7 years after occurrence of first cancer. Two patients had germ-line p53 gene mutation. Anticancer drugs and genetic factors are presumed to be concerned with occurrence of second cancer. The frequency of multiple primary cancers in patients with osteosarcoma is by no means low. Strict follow-up is thus needed over a long period.