Graves’ disease (GD) coincides with the occurrence of disease‐associated intrathyroidal dendritic cells (DC) and intraorbital inflammatory macrophages (Mφ). Physiologically, tumour necrosis factor‐α (TNF‐α) strongly affects the differentiation of DC and Mφ from monocytic precursors; we thus hypothesized that dysregulation of the TNF/TNFR superfamilies may provide a systemic pathogenic link in GD. In patients without eye symptoms, percentages of TNF‐α‐stimulated blood monocytes were highly significantly (P < 0.001) elevated, corresponding to both intrathyroidal DC maturation as well as increases in mature blood DC (MHC‐IIhi/CD40+/RFD1hi) and B cells (CD20hi/CD40+). GD patients also displaying eye symptoms revealed a striking reduction in blood monocytes, yet significantly (P < 0.05) increased CD40hi and TNF‐αhi leucocytes. These findings suggest for GD that excess TNF‐α induces monocytes to differentiate into hyperactivated thyroidal DC that, once emigrated, initiate systemic humoral autoimmunity associated with CD40/TNF‐α upregulation. Such overexpression may instigate differentiation of periorbital inflammatory Mφ from CD14hi/CD16+ monocytes as a likely precursor subset. These results indicate that dysregulation of TNF/TNFR superfamily members provides a systemic pathogenic link in GD in that hyperactivated circulating monocytic precursors give rise to locally restricted, disease‐associated DC and Mφ. Monocytes, therefore, may serve as a suitable target to therapeutically address the common precursor of key promoters of GD.