IL-6 is a multifunctional cytokine that regulates cell growth, differentiation, and cell survival. Many tumor cells produce TGF-β1, which allows them to evade CTL-mediated immune responses. IL-6 antagonizes TGF-β1 inhibition of CD3 cell activation. However, whether IL-6 restores NK activity, which also is suppressed by TGF-β1, is not known. We used canine transmissible venereal tumor (CTVT), which produces TGF-β1, as a model to determine whether IL-6 restores lymphokine-activated killer (LAK) activity. During the progression phase, CTVT cells stop expressing MHC molecules. During the regression phase, the number of surface MHC molecules increases dramatically on about one-third of tumor cells. Tumor cells that stop expressing MHC should be targeted by NK cells. In this study, we found that TGF-β1 secreted by CTVT cells suppressed LAK cytotoxicity. Interestingly, tumor-infiltrating lymphocytes (TIL) isolated from regressing CTVT secrete high concentrations of IL-6 and antagonize the anti-LAK activity of tumor cell TGF-β1. TIL also produce IL-6 during progression phase, but the concentration is too low to block the anti-LAK activity of TGF-β1. There is probably a threshold concentration of IL-6 needed to reverse TGF-β1-inhibited LAK activity. In addition, in the absence of TGF-β1, IL-6 derived from TIL does not promote the activity of LAK. This new mechanism, in which TIL manufacture high concentrations of IL-6 to block tumor TGF-β1 anti-LAK activity, has potential applications in cancer immunotherapy and tumor prognosis.