The circadian pattern of the immune system correlates with that of circulating T-helper cells and inversely with cortisol concentrations. Corticosteroids, both endogenous and exogenous, cause lymphocyte dimunition in blood by retention of cells in the lymphatic circulation. A physiologic pharmacodynamic model was developed to describe changes in circulating lymphocytes as a function of both endogenous cortisol and methylprednisolone concentrations. The model was applied to T-helper and T-suppressor cell data collected from six asthmatic men during baseline, after single-dose, and after 6 days of 20 mg daily methylprednisolone. The model described all phases of the study well. Baseline circadian rhythm of lymphocytes was related to cortisol concentrations. Multiple-dosing of methylprednisolone caused apparent tolerance and decreased the sensitivity of lymphocytes to corticosteroids by 116% and markedly reduced endogenous cortisol concentrations. A 60% increase in circulating T-helper cells was observed which could be accounted for by dual changes in receptor sensitivity and endogenous cortisol.