BACKGROUND Elevation of plasma renin activity (PRA) is a feature of mineralocorticoid deficiency in patients with primary adrenal insufficiency. This study was designed to assess the usefulness of PRA as an index of adequacy of fludrocortisone (FC) replacement in patients with primary adrenal failure, paying particular attention to the variability in PRA levels during FC and glucocorticoid treatment.METHODS Twenty‐two patients with mineralocorticoid deficiency due to primary adrenal disease were studied at 3 time points: 8, 24 and 32 hours following the administration of FC replacement. Body weight, blood pressure while supine and erect, PRA, and plasma or serum levels of aldosterone, urea, sodium and potassium were measured at each time. The clinical and biochemical consequences of adjusting the FC dose were monitored in 5 patients with PRA levels above the range seen in normal subjects and in one hypokalaemic patient with normal PRA levels.RESULTS At 8 and 32 hours following FC administration, PRA levels were not significantly different. PRA levels were significantly higher at 32 hours following FC administration (4.7 ±1.1 nmol/l/h) than at 24 hours (4.2 ±1.1 nmol/l/h, mean ± SEM,P <0.05). At 8 and 32 hours following FC administration, potassium levels were similar. Potassium levels were significantly higher at 32 hours following FC administration (3.9 ± 0.1 mmol/l) than at 24 hours (3.6 ±0.1 mmol/l,P < 0.05). No changes in measurements of sodium, urea, mean supine and erect arterial pressure or body mass index were noted at the different study points. Attempted lowering of elevated PRA in 5 normokalaemic subjects by raising the dose of FC led to normalization of PRA in all of these patients but 2 developed hypokalaemia and oedema. Lowering of FC dose in one hypokalaemic patient with normal PRA levels led to the PRA levels rising to a supranormal value while the hypokalaemia was corrected.CONCLUSIONS These results indicate that when plasma renin activity is estimated in patients with primary adrenal insufficiency replaced with daily doses of fludrocortisone, the time of day of blood sampling is not critical. Lowering elevated plasma renin activity levels to normal in patients who were considered to be otherwise normal may lead to over‐treatment in some patients. Therefore, optimal fludrocortisone replacement may be associated with mildly elevated plasma renin activity levels. The information obtained by monitoring plasma renin activity adds little to the assessment of patients based on clinical evaluation and measure