Background: Syndecans are type-1 heparan sulphate proteoglycans which play significant role in cell-cell and cell-extracellular matrix interaction. Syndecans are involved in tooth development and differentiation of mesenchymal cells. Amongst odontogenic lesions, ameloblastomas and dentigerous cysts are routinely encountered lesions with difference in treatment modality based on its aggressiveness. The objective of the present research was to study and compare immunohistochemical expression of syndecan-1 in ameloblastoma and dentigerous cyst. Method:  40 retrospectively diagnosed cases of ameloblastomas and dentigerous cysts were immunohistochemically stained against syndecan-1. The intensity of immunostaining and percentage of positive cells was assessed by three independent blind observers. Weighted kappa test was used to find out inter-observer reliability. Comparative evaluation of syndecan-1 expression between the two lesions was done using student t-test. Results:  There was statistically significant difference between the mean of score for intensity, mean of score for percentage of positive cells and total mean score of syndecan-1 between ameloblastoma and dentigerous cyst. Conclusion: Syndecan-1 may be involved in aetiopathogenesis of odontogenic lesions like ameloblastoma and dentigerous cyst. Also, weak expression in ameloblastoma indicates that tumor invasion and aggressiveness is related to cell adhesion molecule like syndecan-1.