Primary central nervous system lymphoma (PCNSL) is a lymphoma arising within the brain or spinal cord in the absence of evident localisation outside the central nervous system (CNS). Poor results in the management of relapsed PCNSL justify the need for vigorous initial therapeutic regimens, and chemotherapy should not be reserved for recurrent disease. Chemotherapy (MBACOD scheme) was delivered prior to irradiation in a group of 20 PCNSL patients, another 8 PCNSL patients underwent radiotherapy only, and the overall survival was evaluated. Computed tomography (CT) images in the group of patients treated with chemotherapy, showed there to be 70% complete responders (CR), 15% non-responders (NR) and 15% partial responders (PR). Half of the CR were scheduled for radiotherapy only at tumour recurrence. The median disease-free period and survival time of the whole group treated with early chemotherapy followed by radiotherapy were 24 and 32 months, respectively, but in the subgroup of CR (70%), taking into account also the patients not yet receiving radiotherapy, these were 38 and 48 months, respectively. The disease-free and survival times in the group of CR (75%) of patients treated with radiotherapy only were 13 and 18 months, respectively. At tumour recurrence, CR to chemotherapy had a second disease-free period longer than 2 years after radiotherapy. Our data support the belief that in scheduling the treatment of PCNSL after histological diagnosis, the first step is to devise high-dose chemotherapy with drugs able to cross an intact blood-brain barrier. The results of our primary approach with early chemotherapy in PCNSL support a consensus to continue chemotherapy until tumour recurrence, and only at that event to initiate radiotherapy. It is a challenge and an option worthy of continuing investigation.