Alteration in serum protein concentration is used commonly in clinical practice as a nonspecific indicator of underlying disease or to monitor disease activity. Although hypercortisolemia may affect protein metabolism directly or indirectly, data regarding alterations of levels of serum protein in a large series of patients with Cushing's syndrome (CS) have been lacking. We have now evaluated, retrospectively, the levels of circulating serum albumin, globulins, total proteins, and the albumin to globulin ratio in 99 patients with endogenous CS before, immediately after, and 3, 6, and 12 months following successful treatment. Subjects with concomitant infections or other chronic diseases were excluded from the analysis. Although mean serum albumin and total protein levels were within the normal reference ranges, in general, they gradually increased after treatment with maximal values being reached at 12 months after normalization of hypercortisolemia (P < 0.0001 for both); there were no significant changes in serum globulin levels or in the albumin to globulin ratio. Patients with CS as a whole showed a weak but significant negative correlation between serum albumin and 0900 h cortisol level (r = -0.303; P = 0.0035). In conclusion, our data suggest that CS is associated with a small but significant reduction in circulating serum protein levels, which are restored following treatment of hypercortisolemia, although these changes occur within the reference range. Thus, extreme alterations in serum total protein or albumin levels in patients with CS should alert physicians to the presence of concomitant pathology, and additional specific investigation should be undertaken to elucidate the cause.