Ameloblastoma is the most frequent odontogenic tumor and is considered a benign, but locally invasive, neoplasm with variable clinico-pathological expression. Syndecan-1 is a cell surface proteoglycan that binds cells to the extracellular matrix and its expression is down-regulated in many cellular transformation models. The aims of this study were to examine the pattern of syndecan-1 expression, to evaluate the proliferating activity in a large series of solid/multicystic (SA) and unicystic ameloblastomas (UA), and to study its possible correlation to their biological behavior. Immunohistochemical studies were performed for syndecan-1 (clone MI15) and Ki-67 (clone MIB-1) in 120 ameloblastomas (75 SA and 45 UA). The salient finding was that expression of syndecan-1 was related to the histological subtype of tumors, as there was a lower expression in SA (40.2%) as compared to UA (49.7%) (p<0.05). These findings did not correlate with Ki-67 expression, as this was similar in both types of ameloblastomas. Our results suggest that the reduced expression of syndecan-1 supports the view that SA has a more aggressive biological behavior than the UA. The lack of correlation between reduction of the syndecan-1 and Ki-67 index may be due to the different histomorphologies of both types of ameloblastoma, and more studies are necessary to better understand the role of this protein in the biological behavior of these tumors.