Macrophages are important responders to environmental changes such as secreted factors. Among the secreted factors in injured tissues， the highly conserved endothelial monocyte activating polypeptide II (EMAP II) has been characterized to limit vessel formation， to be locally expressed near sites of injury labeling it a "find-me" signal， and to recruit macrophages and neutrophils. The molecular mechanisms mediated by EMAP II within macrophages once they are recruited are unknown. In this study， using a model of partially activated， recruited thioglycollate-elicited peritoneal macrophages， a transient， transcription profile of key functional genes in macrophages exposed to EMAP II was characterized. We found that EMAP II-mediated changes were elicited mainly through signal transducer and activator of transcription 3 (STAT3) as evidenced by increased Y705 phosphorylation and changes in activity and upstream of it， Janus associated kinase (JAK)1/2 upstream. Both inhibition of JAK1/2 and knockdown of Stat3 abrogated a subset of genes that are upregulated by EMAP II. Our results identify a rapid EMAP II-mediated STAT3 activation that coincides with altered pro- and anti-inflammatory gene expression in macrophages.