Following loss of functional renal mass induced by a single parenteral injection of folic acid, the increased proliferation of tubular epithelium to replace injured and necrotic cells was associated with S6 kinase activation and enhanced phosphorylation of this ribosomal protein in vitro, EGF administered 1.5 h after folic acid promoted the phosphorylation of S6 protein and accelerated the regenerative repair process. In contrast, the hypertrophic response of the kidney following uninephrectomy was not associated with S6 kinase activation. The results of this study suggest a close correlation between levels of S6 protein phosphorylation and the degree of cell proliferation in the rat kidney.