The elderly have impaired cellular immunity and are more predisposed to opportunistic infections after long term glucocorticoid treatment. No data, examining the response of lymphocyte subsets (CD4+, CD8+) under baseline conditions and after exposure to methylprednisolone in young and elderly males, are available. This crossover study examined lymphocyte subsets and cortisol response patterns in seven elderly males (66-82 years) and five young males (24-37 years) randomized into Phase I (24 hr baseline) and Phase II (10 mg intravenous dose of methylprednisolone). Whole blood samples were obtained at 0, 4, 8, 12 and 24 hr to determine total lymphocytes and CD4+ and CD8+ cells utilizing monoclonal antibodies and flow cytometry. The absolute number of lymphocyte subsets and the lymphocyte area under the time curve (AUC) were measured and a 12 and 24 hr lymphocyte response ratio (AUC Phase II divided by AUC Phase I) was determined. Serial plasma samples over 24 hours were collected to quantitate cortisol (Phase I) and methylprednisolone concurrent with cortisol (Phase II). Pharmacokinetic parameters were generated and the cortisol AUC was determined. The AUC values for lymphocytes and cortisol from Phase II quantitated the pharmacologic response to methylprednisolone exposure while Phase I data described the interpatient variability in these parameters. Diurnal patterns for lymphocytes and cortisol were noted in all subjects during Phase I. The mean CD4+ and CD8+ lymphocyte AUC from 0 to 24 hr during Phase I was significantly smaller for the elderly when compared to young men. However, after exposure to methylprednisolone, lymphopenia occurred in all subjects with a mean decline of 54% in the elderly and 60% (p = 0.44) in young subjects for the total lymphocyte count and returned to baseline by 8-12 hr. During Phase II, the CD4+ lymphocytes (72% decline in elderly; 70% in young; p = 0.71) demonstrated a more notable decline than CD8+ cells (44% decline in elderly; 52% in young; p = 0.31) with a nadir occurring between 4 to 6 hr for both subsets. The lymphocyte response ratio was not significantly different between groups for total, CD4+, and CD8+ cells at 12 hr or 24 hr determinations. A slower clearance of methylprednisolone was noted in the elderly (mean: 256 mL/hr/Kg) than in the young men (mean: 359 mL/hr/Kg; p < 0.05) during Phase II with no significant difference found between groups for volume of distribution, elimination rate constant or half-life. A significantly smaller cortisol suppression ratio [0.36+/-0.11 (elderly) versus 0.58+/-0.11 (young), p = 0.01] which indicates a more profound cortisol suppression was noted. A significant correlation of -0.61 (p < 0.05) between drug exposure (methylprednisolone AUC) and pharmacologic effect (cortisol suppression ratio) was noted for the combined data in the young and elderly males. During Phase I, the CD4+ and CD8+ lymphocyte AUC was significantly smaller in the elderly. A definite suppression pattern for total, CD4+ and CD8+ lymphocytes and cortisol was noted after methylprednisolone exposure in young and elderly males. An age-dependent suppression of cortisol during Phase II was noted but the degree of lymphopenia after drug exposure did not differ between the young and elderly group for any of the cell subsets. These data from healthy elderly provide a basis for further studies to assess immunologic and endocrinologic responses among elderly patients requiring chronic glucocorticoid therapy.