Background <p>The purpose of this study was to explore the role of immune modulation and iron metabolism disorder in the pathogenesis of osteoarthritis.</p> Methods <p>We performed a systematic analysis of datasets and immune infiltration of osteoarthritis and healthy cartilage tissues, to obtain differences in genes expression and immune cell infiltration related to iron metabolism between two samples. The iron metabolism-related genes with prognostic value was screened by Lasso and Cox regression, and validated their expression in knee cartilage samples from normal and osteoarthritis patients by immunohistochemistry.</p> Result <p>We obtained 494 differential genes that meet the criteria and 147 genes related to iron metabolism diseases. Many entries have been found, which Wnt signaling pathway and cholesterol metabolism may play key roles in the degradation of cartilage. The immunohistochemical staining on normal and osteoarthritis cartilage showed that iron metabolism-related genes genes were significantly higher expressed in osteoarthritis cartilage than in normal cartilage.</p> Conclusions <p>The iron metabolism imbalance and immune cell subtype infiltration may be associated with the occurrence and progression of osteoarthritis. These results provide a new perspective for understanding the pathophysiology of osteoarthritis, and also offer new ideas for developing more effective treatment strategies.</p>