Seventeen children aged 1.5 to 15.6 years with minimal change nephrotic syndrome (MCNS) had hypothalamic-pituitary-adrenal (HPA) tests performed. The study consisted of baseline cortisol levels (8 a.m. and 4 p.m.), 6-hour ACTH stimulation tests and metyrapone tests. Ten patients were frequent relapsers (4 or more relapses per year) and 7 patients were infrequent relapsers (less than 4 relapses per year). All relapses were treated with daily prednisone 60 mg/m2 until the urine was protein-free for 3 days followed by prednisone 40 mg/m2 every other day for 28 days. All were tested no sooner than 1 week after alternate-day prednisone therapy was discontinued. The morning and afternoon cortisol levels of all frequent relapsers were abnormally low. The average a.m. and p.m. cortisol levels in the frequent relapsers were 2.6 +/- 0.08 and 1.4 +/- 0.4 microgram/dl respectively (normal a.m. value 10-20 microgram/dl, p.m. 50% a.m. value). In the frequent relapsers 9 out of 10 had a normal 6-hour ACTH test and 8 out of 9 had a normal response to metyrapone. In all infrequent relapsers the morning and afternoon cortisols were normal (mean a.m. 12.9 +/- 1.4 and p.m. 6.8 +/- 0.8 microgram/dl). Also, all infrequent relapsers had normal responses to ACTH and metyrapone. It is concluded that low baseline plasma cortisol levels are predictably present in frequent relapsers treated with prednisone.