Among nearly 50,000 cancer patients at the National Cancer Center, about 2,000 have multiple primary cancer (MPC), and its frequency has been increasing in recent years. MPC is considered to be a reflection of severe exposure to carcinogens or of a predisposition to cancer, or sometimes it is thought to be an individual expression within familial aggregation. To clarify the roles of these proposed mechanisms, case-control studies and chromosome analyses, including fragile sites on chromosomes, were performed focusing in particular on breast and lung cancer patients. A histology-matched case-control study of multicentric lung cancer revealed a risk of cigarette smoking, which was also recognized in MPC in different sites among breast cancer patients, in addition to the radiotherapy. The frequency of heritable (rare) fragile sites among 87 lung cancer patients was more than double that of the general population, and the rare fragile site, 17q12, was clustered in the adenocarcinoma. The frequencies of heritable fragile sites among breast cancer patients were the same as the general population. MPC occurred in 10 of 87 lung cancer cases, and in 9 of 90 breast cancer patients; these individuals did not have heritable fragile sites. Heavy smoking and hazardous occupations were recognized in MPC cases with lung cancer, and a family history of rather rare cancers was also more common in MPC cases with breast cancer. One of three triple cancer cases had breast cancer as a feature in chromosomal aberrations of the peripheral blood lymphocytes, which may signify predisposition to cancer in these patients.