We have studied the effects of combination therapy with thymosin alpha 1 and IFN or IL-2 on natural killer cell activity in both normal and immunosuppressed animals after cyclophosphamide treatment and during B-16 melanoma and 3LL tumor growth. Our results suggest that while the combined treatment does not substantially modify the depressed natural killer cell response, thymosin alpha 1 pre-treatment significantly restores the boosting capacity of the two cytokines, IL-2 and IFN. Since thymosin alpha 1 proved capable of accelerating natural killer cell activity recovery in animals irradiated and reconstituted with symgenic marrow cells, we hypothesize that the synergistic effect between thymosin alpha 1 and IFN could result from the differentiation of natural killer cell lines by thymosin alpha 1 which can then become sensitive to IFN. Furthermore, we have demonstrated a good correlation between restoration of natural killer cell activity and regulation of tumor growth. Thus, these results may have important implications in tumor immunotherapy and patients with infectious diseases such as AIDS which is associated with low natural killer cell activity.