Macrophages readily change their phenotype in response to exogenous stimuli. In this work, macrophages were stimulated under a variety of experimental conditions, and phenotypic alterations were correlated with changes in gene expression. We identified three transcriptionally related populations of macrophages with immunoregulatory activity. They were generated by stimulating cells with lipopolysaccharide (LPS), a toll like receptor (TLR) ligand, in the presence of three different "reprogramming" signals; high density immune complexes (IC), prostaglandin E2 (PGE2), or adenosine (Ado). All three of these cell populations produced high levels of transcripts for IL-10, as well as growth and angiogenic factors. They also secreted reduced levels of inflammatory cytokines IL-1B, IL-6, and IL-12. These three activated macrophages could partially rescue mice from lethal endotoxemia, and therefore we consider each to have immunoregulatory activity. This immunoregulatory activity occurred equally well in macrophages from stat6-deficient mice. The lack of STAT6 did not affect macrophages' ability to reciprocally change cytokine production or to rescue mice from lethal endotoxemia. Furthermore, macrophages treated with IL-4 do not exhibit the immunoregulatory phenotype and associated transcriptional alterations. This work demonstrates that there are multiple ways to generate macrophages with immunoregulatory activity. These Regulatory macrophages are transcriptionally and functionally related, and quite distinct from macrophages treated with IL-4.