The NOA-03 trial explored high-dose methotrexate alone in 37 patients with primary central nervous system lymphoma. The overall median survival was 25 months. After 4 years, the rate of leukoencephalopathy in patients surviving more than 12 months was 58% with and 10% without whole-brain radiotherapy given at relapse (p = 0.11). Attention deficits were found in all six tested patients, and memory deficits in four patients. Two patients had normal, three had moderately restricted, and one had markedly restricted quality of life. Thus, high-dose methotrexate with deferred radiotherapy had only moderate efficacy and was associated with significant neurotoxicity in long-term surviving patients.