Investigations into the role of NK cells in regulating Ab responses have yielded variable results, some suggesting that NK cells can down-regulate Ag-specific Ig production and others proposing an enhancing effect. These apparently inconsistent findings may stem partially from the specificity of reagents used in purifying cell populations and/or the nature of the in vitro systems used to study these events. We chose to investigate the ability of either resting or poly(I:C)-activated NK cells to alter an in vivo Ab response in mice given a T-independent (TNP-LPS) or T-dependent (TNP-keyhole limpet hemocyanin (KLH)) Ag. By using a more specific Ab, anti-NK-1.1, to deplete NK cells, we were able to clearly show that resting, endogenous NK cells do not affect either type of response, as measured by serum Ag-specific Ig levels quantitated by isotype-specific ELISA. In contrast, activation of NK cells by poly(I:C) increased Ag-specific IgC2a as well as IgG1 levels. Interestingly, only the effect on IgG2a production is reversible by depletion of NK cells.