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Recent evidence suggests that alterations of the immune responses are associated with the inflammatory nature of obstructive sleep apnea (OSA) and of its related co-morbidities. In this scenario, we asked whether circulating dendritic cell (DC) subsets may be possible players as their role has not yet been detailed. The frequency distribution of peripheral blood myeloid (mDC1 and mDC2) and plasmacytoid (p) DCs was investigated by mean of multi-parametric flow cytometry in 45 OSA patients (mean age: 53 yrs; M = 29) at the time of the first diagnosis and compared to 30 age- and sex-matched healthy controls. Oxidative burst (OB) and serum levels of tumor necrosis factor (TNF)-α, (interleukin) (IL)-6, interferon (INF)-γ, IL-2, IL-4, IL-10 and vascular endothelial growth factor (VEGF) were also analyzed. All subsets of circulating DCs were significantly depleted in OSA patients as compared to healthy subjects (p < 0.01, in all instances), with mDC2 and pDC subtypes being more severely compromised. These findings were co-existing with higher levels of OB along with an increased expression of IL-6, IL-10, TNF-α, IFN-γ, and VEGF (p < 0.005 in all instances). In particular, IL6 levels were significantly higher (p = 0.013) in severe OSA patients (apnea/hypopnea index >30) and were inversely correlated with both mDC2 (r = −0.802, p < 0.007) and pDC (r = −0.317, p = 0.04) subsets. We first provide evidence for a constitutive reduction of all circulating DC subsets in OSA patients. Perturbation of DCs coexists with an inflammatory milieu and is negatively correlated with the expression of IL-6, which is actually recognized as a pivotal inhibitor of DC maturation. Future studies exploring the contribution of DCs in the pathogenesis of OSA and of its complications should be encouraged.