It is well established that after removal of renal mass, the remaining tissue undergoes compensatory growth. Several laboratories have reported that the activity of the apical membrane Na⁺-H⁺ exchanger (NHE3) is increased after a reduction in renal mass. These studies were designed to determine whether NHE3 expression is altered early after loss of renal mass and to investigate the possible role of NHE3 activation in the compensatory tissue growth response. Experiments were performed in young male Wistar rats submitted to left nephrectomy or sham operation. At either 4 or 24 h after the surgery, the right kidney from each animal was removed and weighed. Significant increases in the wet weight of the remaining kidney were only observed 24 h after uninephrectomy (UNX). Western blot analysis of brush-border membranes and Northern blot analysis of cortex RNA showed that NHE3 protein abundance and NHE3 mRNA were greatly enhanced 4 and 24 h after UNX in relation to the sham kidney. To identify which growth pattern was mostly responsible for the enlargement of the remained kidney in our experimental models, we measured 5-bromo-2-deoxyuridine incorporation (BrdU) and protein-to-DNA ratio (protein/DNA ratio). The number of BrdU-positive nuclei increased and protein/DNA ratio slightly decreased, indicating that a hyperplastic response was the main component involved in the early compensatory renal growth in our animals. BrdU incorporation and protein/DNA were also assessed in rats treated with S3226, a selective blocker of NHE3. Neither the number of BrdU-positive nuclei nor the protein/DNA ratio was significantly altered 4 and 24 h after UNX in rats treated with S3226. In conclusion, UNX induced an upregulation of NHE3, which was evidenced at both functional and expression levels. The compensatory growth response in young UNX rats could be blocked by inhibiting NHE3 activity, suggesting that NHE3 activation may result in a facilitator state for the cell growth response in the renal proximal tubule.