Experiments are described that characterize the nature of the stimulus leading to lymphocyte-induced angiogenesis (LIA), a reaction previously shown to reflect a local in vivo graft-vs-host reaction. The studies demonstrate that circulating cells of the host animals provide the stimulation essential for activation of donor lymphocytes and that the major allogeneic stimulus in congenic lines of mice is correlated with I-region disparity, primarily associated with I^A-controlled determinants. The results are readily compartible with the hypothesis that is proposed that LIA is in large part the consequence of the release of soluble mediators or lymphokines that may act either directly on endothelial cells or indirectly by activating macrophages, which in turn generate the vascular reaction.