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OBJECTIVE To examine and compare the immunohistochemical expressions of IL-1β, IL-6, IL-17 and TNF-α in peripheral giant cell granuloma (PGCG) and peripheral ossifying fibroma (POF). DESIGN The study included 20 POF and 20 PGCG cases diagnosed at the Pathology Department of Eskişehir Osmangazi University Medical Faculty. Hematoxylin & Eosin-stained slides obtained from each biopsy specimen were re-evaluated, and IL-1β, IL-6, IL-17 and TNF-α antibodies were investigated immunohistochemically. While staining in stromal cells was examined in POF cases, staining in both stromal spindle cells and multinucleated giant cells was evaluated in PGCG cases. An immunoreactivity score was established for each case by evaluating the staining percentage and intensity for each individual case. The significance level was set at 5% (p < 0.05). RESULTS The level of IL-6 and TNF-α expressions in the multinucleated giant cells in PGCG lesions was found higher than that in stromal cells (p < 0.005 and p < 0.000, respectively). In PGCG lesions, there was no significant difference between giant cells and stromal cells in terms of IL-1β and IL-17 expression levels. There was no significant difference between PGCG and POF lesions in terms of IL-1β and IL-6 expression. TNF-α expression levels were significantly higher in spindle cells of PGCG lesions than that of POF lesions (p < 0.00). However, IL-17 expression levels were significantly lower in PGCG lesions than in POF lesions (p < 0.05). CONCLUSION The study results showed that TNF-α expression was significantly higher in PGCG lesions and IL-17 expression in POF lesions. IL-1β, IL-6, IL-17 and TNF-α are involved in the pathogenesis of both PGCG and POF lesions.