Studies from our laboratory and others have demonstrated that alpha-interferon (IFN alpha) can regulate natural killer cells and lymphokine-activated killer (LAK) cell activation. In vitro experiments have shown that IFN alpha has differential effects on both natural killer cells and LAK activity when combined with interleukin 2 (IL2); IFN alpha synergized with IL2 to augment natural killer cells activity while it suppressed the IL2-induced LAK response. Here we demonstrated that IFN alpha A/D can also regulate IL2-induced LAK activity in vivo with enhanced or suppressed activity depending on the IFN alpha A/D dose. The enhanced response was observed with the combination when 80,000 units/day of IFN alpha A/D were used and was detectable in the spleen, lung, and peritoneum. When a high dose of IFN alpha A/D was combined with IL2, a moderate reduction in LAK activity was noted in the spleen and peritoneum. In contrast, a high dose IFN alpha A/D augmented IL2-induced LAK activity in the lung even though it reduced the level of cellular infiltration. We have also evaluated the effect that IL2, IFN alpha A/D, and IL2 plus IFN alpha A/D have on the frequency of LAK precursors in the spleen and lung using limiting dilution analysis. Treatment of normal mice with IL2 alone increased the frequency of LAK precursor (LAKp) in the lung. This increase was associated with an infiltration of Thy-1+, asialo-GM1+, Lyt-2- lymphocytes into the lungs. Moreover, treatment with IL2 plus IFN alpha A/D enhanced the frequency of LAKp over that observed with IL2 alone. Treatment with the combination did not change the phenotype of LAKp in the lung from that seen with IL2. The increase in LAKp frequency induced by the combined treatment may not be a direct effect of IFN alpha A/D on precursor cells since IFN alpha A/D alone did not increase the frequency of LAKp in vivo or in vitro when added to limiting dilution analysis cultures. In contrast to what occurred in the lung, a consistent increase in LAKp was not seen in the spleen after treatment with IL2 or with the combination, although LAK activity was observed. These results demonstrated that in addition to inducing lytic activity from LAK effectors in vivo, IL2 treatment increased the number of precursor cells within the lung. Moreover, IFN alpha A/D in combination with IL2 influenced the level of LAKp in situ.