We undertook a study to determine whether soy protein feeding would ameliorate renal injury in the Han:SPRD-cy rat model of polycystic kidney disease (PKD). Male offspring of Han:SPRD-cy heterozygotes received isocaloric diets based on 20% casein or 20% heat-treated soy protein at weaning ad libitum for 8 wk. Soy-fed animals demonstrated lower serum creatinine (66 vs. 125 mumol/l; P = 0.002), lower urinary ammonium excretion (0.080 vs. 0.173 mmol/kg; P = 0.01), reduced renal cysts (0.98 vs. 4.92 ml/kg body wt, P < 0.0001), renal fibrosis (0.79 vs. 1.4 ml/kg; P = 0.016), macrophage infiltration, renal tubular cell proliferation, and apoptosis. Proton nuclear magnetic resonance (1H-NMR) studies of urine demonstrated that soy diet was associated with increased losses of citric acid cycle organic anions. 1H-NMR of perchloric acid-extracted tissue found that levels of succinate were not depleted in soy-fed animals, despite increased urinary losses. Soy-fed animals had marked elevation of tissue betaine (P < 0.001), with reduced taurine and cholines, compared with casein-fed animals (P < 0.001). Soy feeding dramatically reduces both tubular and interstitial pathology in the Han:SPRD-cy rat model of PKD, through mechanisms that remain to be determined.