Dehydroepiandrosterone ( DHEA ) is a predominant androgen secreted by the adrenal cortex. Physiologically, DHEA appears as an intermediate of the androgen biosynthesis pathway. However, DHEA has been shown to play a multifunctional role in human and animal body. In addition, DHEA is a potential immunomodulator. DHEA regulates a variety of humoral and cellular immune response. Our previous report suggested that DHEA enhanced immunoglobulin secretion by murine B lymphocytes under in vitro condition. The same study also observed an antagonist effect of DHEA on the dexamethasone ( a glucocorticoid derivative )-mediated immunosuppression. The present study further extended the DHEA study from murine system to human immune cells. Data suggested that DHEA and DHEAS had no significant effect on the growth and viability of non-adherent peripheral blood mononuclear cells ( PMNC ). However, both drugs significantly augmented IgA and IgM secretion. Dexamethasone also enhanced IgA and IgM secretion by PMNC. Under our in vitro experimental condition, costimulating the cells with DHEA/DHEAS and dexmethasone shown a synergistic dffect on IgA and IgM secretion. To further investigate whether DHEA/DHEAS enhanced immunoglobulin secretion by direct stimulating the B lymphocytes, the growth and function of Dakiki ( an IgA secreting cells ) and SKW6.4 ( an IgM secreting cells ) in the presence of DHEA/DHEAS were studied. DHEA and DHEAS had no significant effect on the growth and viability of both Dakiki and SKW6.4. DHEA/DHEAS enhanced IgA and IgM secretion by Dakiki adb SKW6.4 cells, respectively dexamethasone suppressed the IgA secretion by IgA secretion by Dakiki. However, the dexamethasone- mediated suppressive effect could be overcome by both DHEA and DHEAS. In contrast, dexamethsaone enhanced IgM secretion by SKW6.4. Cosimulating the SKW6.4 with DHEA/DHEAS and dexamethasone has synergistic effect on IgM secretion. The IgM gene expression was studied by RT-PCR analysis. Result shown that the mRNA level of IgM in SKW6.4 cells were elevated after the cells were treated with DHEA, DHEAS or dexamethasone, suggesting that IgM production was stimulated at the transcription level.