© 2014 American Academy of Allergy, Asthma & Immunology. Background Subsets of myeloid-derived regulatory cells (MDRCs), which are phenotypically similar to the myeloid-derived suppressor cells found in patients with cancer, have recently been appreciated as critical regulators of airway inflammation in mouse models of asthma. Objective We test the hypothesis that subsets of airway MDRCs contribute differentially to the inflammatory milieu in human asthma and chronic obstructive pulmonary disease (COPD). Methods We used bronchoalveolar lavage to identify and characterize human airway MDRCs from 10 healthy subjects, 9 patients with mild asthma, and 8 patients with COPD, none of whom were treated with inhaled or systemic corticosteroids. We defined subsets of airway MDRCs using flow cytometry, the molecular mediators they produce, and their abilities to regulate proliferation of polyclonally activated autologous T lymphocytes. Results We found substantial differences in the functional potential of MDRC subsets in healthy subjects, patients with asthma, and patients with COPD, with these differences regulated by the nitrosative and oxidative free radicals and cytokines they produced. Nitric oxide-producing MDRCs suppressed and superoxide-producing MDRCs enhanced proliferation of polyclonally activated autologous CD4 T cells. HLA-DR+CD11+CD11c+CD163- superoxide-producing MDRCs, which stimulated proliferation of autologous T cells, comprised a high fraction of MDRCs in the airways of patients with mild asthma or COPD but not those of healthy control subjects. CD11b+CD14+CD16-HLA-DR- nitric oxide-producing MDRCs, which suppressed T-cell proliferation, were present in high numbers in airways of patients with mild asthma but not patients with COPD or healthy control subjects. Conclusion Subsets of airway MDRCs conclusively discriminate patients with mild asthma, patients with COPD, and healthy subjects from each other. The distinctive activities of these MDRCs in patients with asthma or COPD might provide novel targets for new therapeutics for these common disorders.