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Aim: Verrucous carcinoma (VC) is a low-grade rare variant of squamous cell carcinoma (SCC). Syndecan-1 (CD138) is a heparan sulfate proteoglycan which participates in cell-to-cell adhesion and cell-matrix interaction. Being misled by the apparent non-aggressive nature of VC, some clinicians and pathologists believe that this tumor is not an aggressive tumor, not realizing the fact that some of these lesions may contain nests or foci of well-differentiated SCC. This study aimed to assess syndecan-1 expression of VC and detection of micro-invasion in VC using syndecan-1 immunohistochemical (IHC) stain. Methods: Observational analytical study of 34 paraffin block of VC cases and 24 cases of variable grades of oral epithelial dysplasia. Cases were stained by hematoxylin and eosin (H&E) and then IHC stain for syndecan-1 was applied. Nine paraffin blocks from specimens of normal oral mucosa were used as the reference group for syndecan-1 stain positivity. Results: In this study, we found that 32 (94.1%) out of 34 of verrucous carcinoma cases showed loss of syndecan-1 expression. Moreover, highly statistically significant association was found between the presence of suggestive micro-invasion in H&E and loss of syndecan-1 expression in micro-invasive area in the same case. Conclusions: In conclusion, syndecan-1 stain can be used as a biomarker in detection of micro-invasion in verrucous carcinoma. [ABSTRACT FROM AUTHOR]