In a population and family study we have examined the relationship between HLA types, classical congenital adrenal hyperplasia (CAH), and variants of 21 hydroxylase (21 OH) deficiency detected by increased blood levels of 17 hydroxyprogesterone (17 PO) in response to ACTH after overnight suppression with dexamethasone ('short Synacthen test'). In a non-CAH population, 7.7% of subjects were found to have raised 17 PO response suggesting reduced activity of 21 OH. Such subjects with raised 17 PO levels were designated simply as type 2 responders because the relationship with genotype was unknown. Post-ACTH levels of 17 PO were significantly greater in type 2 responders than in obligate carriers of CAH. A total of 2.5% of the population studied also had raised progesterone (PO) levels in the Synacthen test. HLA-A28 and B14 (in linkage disequilibrium) were significantly increased in frequency and HLA-B12 decreased in the type 2 responders. HLA-Bw47, which is known to be associated with CAH, was found only among obligate carriers of classical CAH. Because type 2 response and classical CAH are linked to HLA but are associated with different antigens, it is likely that they are determined by two (or more) alleles.