Background: Gaucher disease (GD) is caused by an autosomal-recessive deficiency of β-glucocerebrosidase leading to an accumulation of glucosylceramide in monocytes/macrophage lineage. We analyzed immune cells and especially the function of dendritic cells to evaluate the potential impact of glucosylceramide accumulation in these cells and its possible role in infections and malignancies usually described in this pathology. These analyses were performed for each patient without and under enzyme replacement therapy. Methods: Seven GD patients were studied and compared with healthy volunteers. Immune cells (B cells, T cells, NK, dendritic cells), were analyzed by flow cytometry directly on whole blood. Cytokine production by blood dendritic cells was assessed after stimulation by toll-like receptor ligands. Cytokines in sera were measured using a multiplex assay. Results: GD patients displayed decreased numbers of NK cells, γδ2 T cells and increased frequency of memory CD4+CD45RO+ T cells, when compared to healthy controls. Numbers of dendritic cells (myeloid (mDC) and plasmacytoid (pDC) dendritic cells) were also decreased. We demonstrated that pDC from GD patients exhibited a decrease in IFNα production after TLR9 stimulation compared to controls. Importantly, enzyme replacement therapy restored pDC function. Finally, we observed an increase of IL-8 and IL-18 in GD patient sera, which were reduced under enzyme replacement therapy. Conclusions: Our data confirm that patients with GD exhibit altered numbers of innate and T lymphocytes and show for the first time that pDC from GD patients exhibit altered responsiveness to TLR9. These alterations could contribute to a decreased response to pathogens and could favor the development of malignancies.