The increased incidence of second malignancies among cancer survivors is well documented. Thus, differential diagnosis between metastatic spread from a prior malignancy and the occurrence of a new neoplasm should be considered. This is particularly difficult for brain lesions due to their poor prognosis that often discourages diagnostic work-up. In some cases diagnosis of a second primary neoplasm, such as primary central nervous system lymphomas (PCNSL), could change the therapeutic management and the prognosis. About 8% of PCNSL occurs as a second malignancy. Homogeneous and intense tomographic enhancement, deep location of lesions and dramatic response to corticosteroids are suggestive for PCNSL and should be carefully considered before the start of treatment for cerebral lesions. Prognosis and standard management of brain metastases and PCNSL are almost completely different. In addition, while treatment of brain metastases often has a palliative purpose the goal in PCNSL treatment is the cure. Four patients with PCNSL as a second malignancy are reported and literature is reviewed. Diagnosis of PCNSL changes the strategy of treatment which could have a critical therapeutic and prognostic impact.