The frequency of AIDS-associated primary central nervous system (PCNS) lymphoma is rapidly increasing in adults and children. In AIDS-related PCNS lymphoma, different authors have reported an overall poorer response rate to conventional radiation compared with immunocompetent patients. This poorer response consists of a significantly positive, although transient effect on survival following radiotherapy (XRT), with a poor toleration for prolonged whole-brain RT (WBR) and with radiation-induced changes within the normal CNS tissue on autopsy examinations after a course of XRT. These observations led us to consider highly focused single-session radiosurgical treatments as a potentially useful therapeutic modality for AIDS-associated PCNS lymphomas. A multi-institutional diagnostic and therapeutic protocol for the evaluation and treatment of AIDS patients with high-risk intracerebral space-occupying lesions has been developed at the University Hospital of Verona. Therapy is based on tumor biopsy. Tumors < or = 3.5 cm in diameter are subjected to Gamma Knife radiosurgery, whereas tumors < or = 4.5 cm are treated with stereotactic brachytherapy. At the Department of Neurosurgery, Verona, Italy, Gamma Knife treatment was performed in 2 cases of deep-seated histologically verified malignant non-Hodgkin's lymphoma. A short-term cliniconeuroradiological follow-up (2 months later) showed neurologic improvement and virtually complete disappearance of the tumor in both patients. The excellent local control and the well-tolerated single-session treatment and absence of brain toxicity signs on CT scan indicate a putative role for Gamma Knife radiosurgery in the treatment of these patients.