Objective: The aim of the study was to evaluate the effect of etanercept immunotherapy on peripheral natural killer (NK) cell activity in women with a history of recurrent miscarriage (RM) or failed in vitro fertilization (IVF). Materials and methods: Thirty nonpregnant women with reproductive failure and increased peripheral NK-cell number and/or activity before conception were studied. Women with reproductive failure received 4 doses (25 mg) of etanercept twice weekly before conception. Peripheral NK-cell activity before and after etanercept therapy in RM women was measured using flow cytometry. In addition, the peripheral blood NK-cell surface antigens- CD16- and CD56 and peripheral blood regulatory T cell (T reg) antigens- CD4- and CD25 were studied using flow cytometry, before treatment and 2 weeks after the last etanercept dose. Results: NK-cell activity was significantly decreased after etanercept therapy in the study women (P<.05). This effect was significantly higher in women with subsequent pregnancy success (P<.05), but not in those with pregnancy failure (P>.05). There were no significant differences in T reg level before and after etanercept therapy (P>0.05). Conclusion: Etanercept therapy might be effective treatment for women with increased NK-cell activity. Regulation of immune system activity may underlie the possible effect of such therapy.