It is becoming apparent that severe stress leads to a reduction in 19C-steroid production in the adrenals of humans. Based on the finding in a prior study of high levels of cortisol (F) and subnormal levels of dehydroepiandrosterone sulfate (DS) in umbilical cord serum of newborns having congenital syphilis, we sought to investigate adrenal function in adult men having syphilis and sera from 30 normal men who were pair-matched with the syphilitic men for age and time of blood sampling were compared with respect to their concentrations of DS and F and the DS to F ratio. Serum levels of F (nmol/liter) were significantly higher in syphilitic men (322 +/- 25) than in control men (226 +/- 16), P = 0.0018. Serum DS levels (mumol/liter) were significantly reduced in syphilitic men (5.80 +/- 0.80) compared with normal men (9.84 +/- 0.94), P = 0.0018. Also, the DS to F ratio in syphilitic men was less than 50% than that of the control men, P = 0.0001). Men having advanced (secondary) syphilis had the greatest alteration in adrenocortical function. We hypothesize that the apparent divergence in adrenal production of DS compared with that of F probably is due to factors other than altered pituitary production of adrenocorticotropic hormone, because patterns of adrenal DS and F production similar to those in syphilitic men have been observed by others to occur in conditions of excessive as well as subnormal pituitary adrenocorticotropic hormone secretion.