Background. Renal damage from hypertension is the second most common cause of end-stage renal failure in the United States. The pathogenesis of this process is incompletely understood. The Dahl/Rapp salt-sensitive (S) rat is a model of lowrenin hypertension, but these rats also develop renal lesions that are virtually identical to human hypertensive nephrosclerosis. Methods. To explore apoptosis as a mechanism of progressive renal injury in S rats, age- and sex-matched S and Sprague-Dawley (SD) rats were placed on either 0.3 or 8.0% NaCl diets, which were continued for 21 days. Results. At day 7, renal histology appeared relatively normal, but by day 21 on the high-salt diet, S rats displayed morphological evidence of severe renal injury that included glomerulosclerosis, arteriolosclerosis, and tubulointerstitial damage. Apoptosis was demonstrated in kidneys of hypertensive S rats by day 7. Cytoplasmic content of cytochrome c was increased in the kidney cortex of hypertensive S rats, and isolated mitochondria showed inappropriate release of cytochrome c sufficient to activate caspase-3 in vitro. Activation of caspase-9 and caspase-3 was observed only in kidney cortex from hypertensive S rats. Conclusions. Kidneys from hypertensive S rats display apoptosis related to mitochondrial release of cytochrome c and activation of caspase-9 and caspase-3. The findings support a primary role of cytochrome c release and apoptosis in the pathogenesis of hypertensive nephrosclerosis in S rats.