Tumor‐specific immunosuppression is frequently observed in tumor‐bearing hosts. Exosomes are nano‐sized, endosomal‐derived membrane vesicles secreted by most tumor and hematopoietic cells and have been shown to actively participate in immune regulation. We previously demonstrated that antigen‐specific immunosuppressive exosomes could be isolated from the blood plasma of antigen‐immunized mice. Here, we demonstrate that plasma‐derived exosomes isolated from mice bearing OVA‐expressing tumors were able to suppress OVA‐specific immune responses in a mouse delayed‐type hypersensitivity model. Enrichment of tumor‐derived exosomes in the plasma of mice bearing subcutaneous melanoma was not detected using an exosome‐tagging approach. Instead, depletion of MHC class II⁺ vesicles from plasma‐derived exosomes or using plasma‐derived exosomes isolated from MHC class II‐deficient mice resulted in significant abrogation of the suppressive effect. These results demonstrate that circulating host‐derived, MHC class II⁺ exosomes in tumor‐bearing hosts are able to suppress the immune response specific to tumor antigens.