Interaction of the ubiquitously expressed molecule CD200 with its receptor(s) CD200R, expressed on cells of myeloid and lymphoid origin, delivers immunoregulatory signals that modulate inflammation in a number of diseases, including transplant rejection and arthritis. A number of isoforms of CD200R have been described in mice with distinct function. We have synthesized small (9-13 mer) peptides defining distinct regions of CD200, and asked whether different peptides would function as agonists and/or antagonists of different CD200R isoforms. The assays used to characterize these functions include a model of inflammation and tumor necrosis factor-alpha production induced following lipopolysaccharide administration in vivo, and mixed leukocyte cultures in vitro. Discrete agonist and antagonist peptides were defined for different CD200Rs, which suggests this approach may have some clinical utility.