Background <p>Various inflammatory and anti-inflammatory mediators, along with diverse cell types, are implicated in the development and progression of periapical lesions. This work aimed to assess the immuno-expression of transforming growth factor-beta 1 (TGF-β1) and CD68 (a macrophage marker), elucidating their roles and potential correlations. Additionally, histological analysis was conducted to evaluate the intensity of inflammatory infiltrates in chronic periapical lesion samples.</p> Methods <p>Tissue samples from fifty individuals with chronic periapical lesions [25 radicular cysts (RCs) and 25 periapical granulomas (PGs)] were obtained, along with control samples from four healthy third molars’ dental pulp. Histological examination and inflammatory infiltrate categorization were performed. Immunohistochemical analysis of TGF-β1 and CD68 markers, along with morphometric assessment, were conducted.</p> Results <p>The control group displayed normal, inflammation-free pulp tissues, while intense inflammation was observed in PGs and RCs (Score 4 and 3, respectively) dominated by macrophages, plasma cells, and lymphocytes. Immunohistochemistry showed higher TGF-β1 and CD68 expression in PGs and RCs versus control (<i>P</i> &lt; 0.001). Moreover, PGs exhibited greater TGF-β1 and CD68 expression than RCs (<i>P</i> &lt; 0.001). However, a negative relationship was detected between the 2 markers (<i>P</i> &lt; 0.05).</p> Conclusions <p>This study highlighted varying expressions of TGF-β1 and CD68 in PGs and RCs, indicating their potential roles in lesion pathology. However, a negative correlation between these markers was observed. Accordingly, their precise role in periapical lesion progression and repair requires further investigation.</p>