Large adrenal tumors are rarely associated with adrenal enzymatic deficiency, except in 11-ss-hydroxylase insufficiency. These tumors are exceptionally malignant. We report here the case of a patient with a congenital 21-hydroxylase deficiency (compound heterozygote for two severe mutations in the CYP21A2 gene) untreated for 20 years. His evaluation at 36 years of age showed a four-centimeter mass in the left adrenal gland, with most characteristics suggestive of malignancy (CT and positron emission tomography [PET] scan). We performed a surgical resection that established the diagnosis of adrenocortical tumor of uncertain prognosis (Weiss's score: 3). Even though malignant tumors are unusual in adrenal deficiency, our observation shows the need for a replacement therapy during adulthood, with a regular CT scan follow up in order to diagnose early isolated adrenal adenoma and remove it in case of malignancy suspicion.