The function of purified ICAM-1 in costimulating CD4+ and CD8+ T cell responses has been directly compared to that of B7-1 in a model system that minimizes contributions of other receptor-ligand interactions. While B7-1 costimulates both subsets of T cells, ICAM-1 is much more effective in the costimulation of CD8+ cells. ICAM-1 also synergizes with B7-1 for the induction of IL-2 production in CD8+ but not CD4+ T cells. These differences are not explained by differences in LFA-1 receptor expression on the two subsets of T cells. The CD8+ T cell response to ICAM-1 costimulation is associated with increased proliferation and IL-2 production at levels similar to those seen with B7-1 costimulation, but clonal expansion in response to ICAM-1 is not as great due to decreased cell survival. ICAM-1-mediated costimulation is effective for both naive and memory CT8+ T cells, is independent of CD28 engagement, and does not appear to be due solely to effects on adhesion. These results suggest that ICAM-1-dependent, B7-independent costimulation may be important in initiating a CTL response to class I antigen presented by cells that are not professional APC.