T cell activation is known to depend not only on efficient antigen recognition and subsequent signaling through TCR, but also on interactions involving multiple adhesion and accessory molecules such as CD28/B7, LFA‐1/ICAM‐1 and LFA‐3/CD2. The present study dissects the role of LFA‐3/CD2 interactions in the activation of melanoma‐specific CD8⁺ T cell clones. To this end we analyzed the influence of LFA‐3 density on melanoma cells on lysis and cytokine production (TNF, IL‐2, IFN‐γ) by T cells following activation by various amounts of antigenic peptides. Our results indicate that increasing LFA‐3 density on melanoma cells variably affects their lysis susceptibility, but systematically and considerably enhances cytokine production by melanoma‐specific cytotoxic T lymphocyte (CTL) clones. At any stimulatory antigen density, LFA‐3 increased the fraction of responding cells and/or cytokine amounts produced by individual cells, without affecting TCR down‐regulation. These results show that CD2 engagement increases cytokine gene activation essentially by providing to T cells a TCR‐independent co‐activation signal. From a practical point of view, our data demonstrate that the level of LFA‐3 expressed on tumors critically affects cytokine production by specific CTL and thus the efficiency of specific immune reactions mediated by these cells.