The nephrotoxicity of low-dose methotrexate (MTX) and the rescue effect of leucovorin were studied by electron-microscopic examination of the kidney of guinea pigs. One group received MTX as a single weekly dose of 10 mg/kg, i.p.; a second group received a similar dose divided into three equal fractions. The third group received MTX rescued with an equal dose of leucovorin. The distal convoluted tubule showed cell swelling, fragmentation of the endoplasmic reticulum and loss of mitochondrial cristae and matrix. Leucovorin minimized these changes. The proximal tubule and the glomerulus were not affected. Low-dose MTX induced a nephrotoxicity in the distal convoluted tubule which could be minimized by leucovorin. Mild myelosuppression was also observed.