Although high-dose methotrexate (HD-MTX) is the most effective drug against primary CNS lymphomas (PCNSL), outcome-determining variables related to its administration schedule have not been defined. The impact on toxicity and outcome of the area under the curve (AUC(MTX)), dose intensity (DI(MTX)) and infusion rate (IR(MTX)) of MTX and plasmatic creatinine clearance (CL(crea)) was investigated in a retrospective series of 45 PCNSL patients treated with three different HD-MTX-based combinations. Anticonvulsants were administered in 31 pts (69%). Age >60 years, anticonvulsant therapy, slow IR(MTX) (</=800 mgm(-2)h(-1)), and reduced DI(MTX) (</=1000 mgm(-2)wk(-1)) were significantly correlated with low AUC(MTX) values. Seven patients (16%) experienced severe toxicity, which was independently associated with slow CL(crea). A total of 18 (40%) patients achieved complete remission after chemotherapy, which was independently associated with slow CL(crea). In all, 22 patients were alive at a median follow-up of 31 months, with a 3-year OS of 40+/-9%; slow CL(crea) and AUC(MTX) >1100 micromol hl(-1) were independently associated with a better survival. Slow CL(crea) and high AUC(MTX) are favourable outcome-determining factors in PCNSL, while slow CL(crea) is significantly related to higher toxicity. AUC(MTX) significantly correlates with age, anticonvulsant therapy, IR(MTX), and DI(MTX). These findings, which seem to support the choice of an MTX dose >/=3 gm(-2) in a 4-6-h infusion, every 3-4 weeks, deserve to be assessed prospectively in future trials. MTX dose adjustments in patients with fast CL(crea) should be investigated.