CD200 receptor 1 (CD200R) is an inhibitory immunoreceptor that suppresses Toll-like receptor (TLR)–induced cytokine production through the adaptor protein Dok2 and the GTPase activating protein (GAP) p120-RasGAP, which can be cleaved during mild cellular stress. We found that in the presence of cleaved p120-RasGAP, CD200R lost its capacity to inhibit phosphorylation of ribosomal S6 protein (rpS6), suggesting the reduced activity of mammalian target of rapamycin complex 1 (mTORC1). Furthermore, treatment of human peripheral blood mononuclear cells (PBMC) with interferon-α (IFN-α) resulted in increased amounts of cleaved p120-RasGAP. Upon pretreatment of cells with increasing concentrations of IFN-α, CD200R switched from inhibiting to potentiating the TLR7- and TLR8-induced expression of the gene encoding IFN-γ, a cytokine that is important for innate and adaptive immunity and is implicated in systemic lupus erythematosus (SLE) pathogenesis. PBMC from patients with SLE, a prototypic type I IFN disease, had an increased abundance of cleaved p120-RasGAP compared to that in cells from healthy controls. In a subset of SLE patients, CD200R stopped functioning as an inhibitory receptor or potentiated TLR-induced IFNG mRNA expression. Thus, our data suggest that type I IFN rewires CD200R signaling to be proinflammatory, which could contribute to the perpetuation of inflammation in patients with SLE.