The effect of prednisolone on renal handling of sodium (Na) was studied in rats under three experimental conditions: 1) hydropenia, 2) water diuresis, and 3) distal tubular blockade (DTB). Prednisolone, 0.25 mg/100 g per hr, was infused directly into left renal artery and urine was collected separately from each kidney. Predominantly unilateral increases in urine flow (V) and Na excretion were noticed in all experiments during prednisolone infusion. In the hydropenic rats the maximal increments on the infused side were, for V (mean ± SD), from 9.3 ± 1.5 to 21.4 ± 0.8 μl/min (P < 0.001); for C(Na)/C(In), from 0.28 ± 0.11 to 2.97 ± 0.71 % (P < 0.005); and for [Formula: see text] , from 2.93 ± 2.26 to 5.32 ± 1.92% (P < 0.05). In the rats with water diuresis, the maximal increases were, for V/C(In), from 5.87 ± 1.97 to 10.1 ± 6.0% (P < 0.005); for C(H(2)O)/C(In), from 4.09 ± 0.68 to 6.00 ± 0.44% (P < 0.0005); and for C(Na)/C(In), from 0.22 ± 0.07 to 0.70 ± 0.38% (P < 0.01). In DTB-rats the maximal increases were for V from 48.6 ± 9.0 to 72.7 ± 14.1 μl/min (P < 0.0005) and for C(Na)/C(In) from 9.42 ± 2.97 to 20.23 ± 7.34% (P < 0.005). In the contralateral kidney these changes were less pronounced. These observations suggest that prednisolone depresses directly Na reabsorption. The association of natriuresis with augmented [Formula: see text] and C(H(2)O)/C(In) during hydropenia and water diuresis, respectively, and the increases in V and C(Na)/C(In) during DTB, all are consistent with inhibition of Na reabsorption in the proximal tubule