Tetrahydrocortisol (H4F) and tetrahydrocortisone (H4E) were determined for a group of 15 depressed patients and 25 normal controls following the administration of cortisol-4-C14. The ratio, H4F/H4E, was significantly greater for the depressed patients than for the normal controls (P < 0.001), although the sum of the two metabolites, H4F + H4E, was not significantly different. Three of four objective test measures of depressive feelings likewise discriminated between the two groups. All four depression measures correlated significantly with the H4F/H4E ratio at the 0.01 level or better. It is suggested that the data of the present report and those of Zumoff et al. (J Clin Endocrinol Metab 39:1120, 1974) may be explained by the paradigm: depressive feelings → reduced thyroid function → elevated H4F/H4E ratio.