GnRH-I and its receptor (GnRHR-I) have previously been demonstrated and shown to be biologically active in the immune system, notably within T cells. Recently however a second form of GnRH (GnRH-II) has been described in the human. The function of both these neuropeptides in B lymphocytes has not previously been explored. The present study investigates GnRH-I and GnRH-II expression in human peripheral mononuclear blood cells (PMBCs) and B lymphoblastoid cells (B-LCLs), as well as their action in regulating B-LCL proliferation in the presence and absence of interleukin-2 (IL-2), both in GnRHR-I mutated lymphocytes and in a normal control. RT-PCR and immunocytochemistry identified locally produced GnRH-I and GnRH-II in all cell groups. Treatment of normal B-LCLs with GnRH-I (10 (-9) M and 10 (-5) M) or with interleukin-2 (IL-2) (50 IU/ml) resulted in a significant increase in cell proliferation compared with the untreated control. IL-2 and GnRH-I (10 (-7) M, 10 (-6) M, 10 (-5) M) induced greater proliferation in normal B-LCLs than IL-2 treatment alone. No significant proliferation occurred in GnRHR-I defective B-LCLs, in response to either GnRH-I (10 (-9) and 10 (-5) M) or IL-2 treatment, nor to IL-2 and GnRH-I (10 (-10) to 10 (-5) M) co-treatment when compared to controls. Co-incubation of IL-2 and IL-2 + GnRH 10 (-5) M with a GnRH antagonist (Cetrorelix; 10 (-6) M) significantly attenuated the proliferation in normal B-LCLs. GnRH-II did not affect proliferation of normal B-LCLs alone, and did not alter the proliferative response to IL-2. Further investigation is required to clarify the physiological relevance of local GnRH-I/GnRH-II in immune system responsiveness.