Primary central nervous system lymphoma (PCNSL) is a rare neoplasm, but it is occurring with increased frequency even among apparently immunocompetent patients. Although secondary malignancies frequently involve the lymphoreticular system, PCNSL has been reported as a second neoplasm only once previously. Seven patients are discussed who developed PCNSL after successful treatment for a prior neoplasm. The original cancer was colon (one), breast (one), thyroid (one), Hodgkin's disease (two), and non-Hodgkin's lymphoma (two). Patients with systemic non-Hodgkin's lymphoma were thought to have a separate cerebral lymphoma on the basis of a prolonged disease-free interval from their systemic lymphoma, and the absence of systemic disease, when PCNSL was diagnosed and through subsequent follow-up. The PCNSL developed a median of 10 years after the diagnosis of the first tumor and 6 years after the last evidence of systemic disease. The diagnosis of PCNSL was often delayed because of confusion with brain metastases, and initial shrinkage or disappearance of the lesion after corticosteroids. Formation of PCNSL may be a consequence of treatment for the first malignancy, reflect an unidentified inherent predisposition to neoplastic transformation, or result from the changing epidemiology of PCNSL in the general population. These mechanisms are not mutually exclusive, and a single hypothesis cannot account for all these cases.