BACKGROUND: Emerging data indicate that the cellular microenvironment and interleukins (IL) play a crucial role in mycosis fungoides (MF). We aimed to explore the potential association between the composition of the cellular microenvironment and the expression of IL-22 and IL-17A in MF skin lesions. METHODS: The study encompassed 16 cases of MF of different stages, for which sufficient skin tissue for immunohistochemistry and frozen tissue for reverse transcription-polymerase chain reaction, both taken from the same lesion, were available. Histological evaluation of eosinophils, neutrophils, CD20+, CD4+, CD8+, FOXP3+, CD56+, and CD1a+ cells was conducted. Additionally, mRNA expression levels of IL-22 and IL-17 mRNA were quantified using reverse transcription-quantitative polymerase chain reaction. SPSS version 28 (IBM Corp., Armonk, NY) was utilized for statistical analysis. RESULTS: Among the cases examined, three were in the patch stage, eight in the plaque stage, and five in the transformation to high-grade large cell lymphoma (t-LCL). B-lymphocytes, neutrophils, and eosinophils were primarily observed in t-LCL cases. IL-22 levels displayed a significant association with IL-17A levels (Pearson's r = 0.961, p < 0.001), FOXP3+ cells (Pearson's r = 0.851, p < 0.001), and neutrophil density (Pearson's r = 0.586, p = 0.014). No correlation was detected between IL-17A levels and the evaluated subtypes of microenvironmental cells. CONCLUSION: The microenvironment of MF lesions with t-LCL is noticeably different from early MF in terms of cellular composition. Histopathological identification of the cellular microenvironment may serve as an indicator of IL-22 tissue levels. These results implicate certain types of cells in IL-22 expression in the MF microenvironment and may contribute to advancing our knowledge on the pathogenesis and progression of the disease.