Background: Graves' orbitopathy (GO) is a complication of Graves' disease characterized by periorbital tissue inflammation, adipose tissue expansion, and fibrosis. The infiltration of immune cells into the periorbital tissue is thought to be a crucial factor in triggering the complication. Although orbital fibroblasts are considered to represent key cellular elements in the pathogenesis of GO, their interaction with immune cells is hardly explored. Here, we aimed to study Methods: Orbital fibroblasts and PBMCs collected from active and inactive GO patients were co-cultured for 48 h in the presence of vitamin D3 and/or steroids (methylprednisolone, MP). Flow cytometric, quantitative PCR (qPCR), and immunoenzymatic assessments enabled evaluation of the changes during cell-to-cell interactions. Results: We found that orbital fibroblasts from inactive GO exhibited higher expression of the genes associated with tissue remodeling. Co-culture of fibroblasts with PBMCs enhanced the proliferation rate of fibroblasts, especially the fibroblasts from active GO. Moreover, the cytokine secretion patterns and early changes in the deposition of extracellular matrix compounds by orbital fibroblasts were also found to differ between disease stages. In addition, we demonstrate that exposure to MP reduces fibroblast proliferation, particularly those derived from the inactive disease stage, and that the combination of MP with vitamin D3 suppresses IL-6 and CCL-20 secretion. Conclusion: We propose that the pathogenesis of GO involves mutual interactions between orbital fibroblasts and immune cells, which may be disease stage-specific and can be modulated by MP and vitamin D3.