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The brains of 20-week-old rats were locally irradiated with single doses of X-rays (400-1400 cGy). A similar group of animals received an intraventricular injection of methotrexate (MTX) prior to irradiation with single doses of X-rays (600-1400 cGy). Animals were killed six weeks after irradiation. A group of unirradiated age-matched animals acted as controls. In irradiated animals, the most severe effect on the subependymal plate (SEP) of the brain was denoted by the fall in the mitotic count (MC) and the number of small dark (SD) nucleated cells. SD nucleated cells are believed to represent the proliferative compartment of the subependymal layer. Other cell types in the SEP, believed to arise from the SD nucleated population, were affected to a lesser degree. After combination treatment with MTX, the decline in the MC and the SD nuclear density was more severe. The data for the dose-related decline in SD nuclear density and the MC fitted equally well on log-linear and linear plots. From the log-linear plots of the data it was concluded that MTX was radiation dose modifying (DMF 1.25-1.44). However, on the basis of the linear plots the effect of radiation and MTX was apparently additive. While no firm conclusions could be drawn regarding the mechanism of action of MTX on the radiation response of SEP cells, the possible mechanisms are discussed.