The effects of cortisol on proliferation and apoptosis of tilapia surface immunoglobulin positive ($sIg^+$) lymphocytes isolated from different tissues were investigated. $sIg^+$ lymphocytes from the tilapia head kidney (HK) and spleen showed a higher proliferation and lower intracellular calcium ($Ca^{2+}{_i}$) level to Ig-crosslinking compared with peripheral blood $sIg^+$ lymphocytes. Peripheral blood $sIg^+$ lymphocytes stimulated with lipopolysaccharide (LPS) showed high levels of apoptosis in the presence of cortisol. HK and to a lesser extent spleen $sIg^+$ lymphocytes, although less sensitive than their equivalent in peripheral blood, showed cortisol-induced apoptosis irrespective of LPS stimulation of control levels. Compared to plasma values measured during stress conditions, proliferation regardless of LPS stimulation was apparently suppressed by cortisol that is effective in inducing a significant increase in apoptosis in all three different cell populations of $sIg^+$ cells, suggesting the immunoregulatory effect of cortisol in both LPS stimulated and non-stimulated conditions. Different sensitivity of $sIg^+$ cells to the cortisol, in regard to developmental stage and activity, could be related in inhibiting excessive and continuing depletion of $sIg^+$ lymphocytes.