Four of 13 patients receiving intermittent high-dose methotrexate therapy experienced recurrent symptoms of ocular irritation (burning, pruritus, "dry eyes") two to seven days after chemotherapy. Ophthalmic examination was unremarkable in symptomatic individuals except for decreased reflex production of tears in some patients. Pharmacokinetic studies of a group of these patients revealed concentrations of methotrexate in tears equivalent to those in plasma at 24 and 48 hours after treatment; these concentrations reached 1 X 10(-5) M during the infusion of methotrexate. The occurrence of acidic lacrimal secretions, pH 6.5 in one symptomatic patient, may have contributed to decreased solubility of methotrexate in the fluid of the conjunctival sac.