Hydrocortisone acetate is usually employed in the treatment of classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. In Brazil, however, oral hydrocortisone acetate is only available from manipulation pharmacies. Prednisolone has stable oral pharmaceutical formulations commercially available, with the advantage of a single daily dose. The aim of this study was to compare the efficacy of oral prednisolone and oral hydrocortisone in the treatment of CAH due to 21-hydroxylase deficiency. Fifteen patients with mean (SD) chronological age of 7.2 (3.6) years, were evaluated in two consecutive 1-year periods. In the first year, hydrocortisone (17.5 mg/m2/day, divided in three doses) was used in the treatment, followed by the use of prednisolone (3 mg/m2/day, once in the morning) in the second year. The comparison between the two treatments was assessed after a one-year treatment period by: variation of height standard deviation score (SDS) (delta Height SDS), variation of height SDS according to bone age (delta BA SDS), variation of body mass SDS (delta BMI SDS) and serum levels of androstenedione. No significant difference was observed in relation to the delta Height SDS, delta BA SDS and delta BMI SDS. No significant difference was observed in the serum levels of androstenedione. We conclude that the efficacy of prednisolone administered once a day orally is comparable to the oral use of hydrocortisone three times a day. Oral prednisolone may be an option for patients with CAH due to 21-hydroxylase deficiency.