Central nervous system (CNS) toxicity from low-dose methotrexate (MTX) has been reported rarely, and reported symptoms consist primarily of dizziness and headache. We reviewed the records of 25 consecutive patients treated with low-dose MTX, and found 5 who had spontaneously reported unpleasant cranial sensations, mood alteration, or memory impairment. Rechallenge with MTX on 5 occasions in 3 patients led to recurrent CNS symptoms in all cases. CNS toxicity was the sole reason for discontinuation of MTX in 2 patients. These 5 patients differed from the 20 without CNS toxicity in age (mean 68 versus 50) and baseline serum creatinine level (1.3 mg/dl versus 0.9 mg/dl), but not in weekly dosage of MTX (12 mg versus 16 mg). These results suggest that CNS toxicity is more common than previously reported, particularly in older patients with mild renal insufficiency.