The renal effects of an acute extracellular fluid volume expansion (50 ml Ringer/kg body weight/60 min) were studied in aldosterone-treated (100 microgram/kg), anesthetized rabbits with and without pretreatment with either indomethacin (3.0 mg/kg) or diclofenac sodium (3.0 mg/kg), two different inhibitors of renal prostaglandin (PG) biosynthesis. In controls (n = 7), the volume expansion increased urine flow from 1.5 +/- 0.24 to 6.1 +/- 0.5 (S.E.) ml/min/100 g kidney weight and sodium excretion from 0.15 +/- 0.03 to 0.99 +/- 0.10 mmol/min/100 g. PAH and inulin clearance increased by 42 and 58%, respectively, while plasma renin activity and urinary excretion of PGF2 alpha-like immunoreactivity were reduced (P less than 0.05). In animals pretreated with indomethacin (n = 6) or diclofenac sodium (n = 6), the diuresis and the natriuresis following volume expansion were significantly increased about two-fold over controls, whereas PAH and inulin clearance, plasma renin activity and hematocrit did not differ from controls. Both drugs were found to reduce urinary excretion of PGF2 alpha-like immunoreactivity by 75--95% througout the experiment. The results indicate that diclofenac sodium, indomethacin and extracellular volume expansion enhance sodium and water excretion partly by suppression of a PG sensitive reabsorption process in the kidney.