Interleukin-15 shares several functional properties with interleukin-2, and signals through the beta and gamma chain of the interleukin-2 receptor as well as through its own high affinity alpha chain. In agreement with the concept that interleukin-2 plays a key role in type IV immune responses, we have recently shown that an IL-2-IgG2b fusion protein potently suppresses Th1-type delayed type hypersensitivity reaction and Th2-type allergic sensitization in mice. We have now compared the in vivo effects of IL-2-IgG2b fusion protein with those of IL-15-IgG2b fusion protein in a murine model of Th1-type contact hypersensitivity reaction. Daily systemic injections of IL-2-IgG2b fusion protein during the sensitization phase or application of IL-2-IgG2b fusion protein just 2 h before and 10 h after antigen challenge significantly inhibited the contact hypersensitivity ear swelling response, and this without any overt signs of associated toxicity. Even local injection of IL-2-IgG2b fusion protein into the earlobe around the time of antigen challenge inhibited the ear swelling reaction significantly. In contrast, neither systemic nor local injection of the IL-15-IgG2b fusion protein modulated the contact hypersensitivity reaction significantly. IL-2-IgG2b but not IL-15-IgG2b fusion protein reduced migration of antigen-presenting cells from the skin to local lymph nodes, inhibited the expression of CD80 and CD86, and induced a significant higher number of CD4+CD25+ T cells. Therefore, the IL-2-IgGb fusion protein offers a powerful tool for suppressing and/or preventing T-cell-mediated hypersensitivity reaction in vivo.