Graves’ ophthalmopathy (GO) is a potentially sight-threatening ocular disease, occurring in patients with hyperthyroidism due to Graves’ disease. Also known as thyroid-associated ophthalmopathy, GO is characterised by orbital infiltration by immune cells including macrophages, T cells and plasma cells, which produce cytokines and growth factors that cause orbital fibroblasts to proliferate and differentiate leading to fibrosis. Mast cells are well-known for their role in allergic and atopic conditions but recent evidence has linked these cells to inflammatory diseases including arthritis, psoriasis and multiple sclerosis. Mast cells, on activation by IgE, release a myriad of products of which histamine is one of the best studied, inducing vasodilation, bronchoconstriction and smooth muscle contraction, in allergic reactions. Mast cells have been reported to be in close proximity to orbital fibroblasts and show features of degranulation in (thyroid-associated orbitopathy) TAO, and serum levels of IgE are increased in patients with GO. In the present study histamine was shown to induce production of IL-6, IL-8 and CCL2 by orbital fibroblasts from patients with GO and three healthy control samples via NF-κB. Interestingly, histamine had no effect on several other proinflammatory cytokines measured or hyaluronin. Orbital fibroblasts expressed histamine receptor 1 and the direct effect of challenge was blocked by specific HRH1 inhibitor. This data, although on a small number of samples, provides important evidence of a role for mast cells and histamine in GO. The effect of other mast cell products on orbital fibroblasts should be investigated.