Background:  Actinic cheilitis (AC) is an oral pre‐cancerous lesion that sometimes develops into lip squamous cell carcinoma (SCC). Syndecan‐1, a transmembrane heparan sulfate proteoglycan, modulates cell‐proliferation, adhesion, migration and angiogenesis. Malignant epithelial cells often down‐regulate their own syndecan‐1 production, and are capable of inducing aberrant syndecan‐1 expression in stromal cells. The aim of this study was to evaluate the variations in syndecan‐1 expression during lip carcinogenesis, in normal lip (NL), AC and well‐differentiated lip SCC.Methods:  Biopsies of NL vermillion (n = 19), AC (n = 23) and lip SCC (n = 24) were stained immunohistochemically for syndecan‐1.Results:  Syndecan‐1 expression was significantly reduced in AC and lip SCC as compared to NL (P < 0.05), with a significant reduction in lip SCC as compared to AC (P < 0.0001). In lip SCC lesions, syndecan‐1 expression at the epithelium overlying the tumor was increased when compared to the tumor itself (P < 0.03), but was significantly reduced as compared to AC and NL (P < 0.001).Conclusion:  The results showed that epithelial syndecan‐1 expression is reduced as lip carcinogenesis progresses (NL>AC>lip SCC), suggesting that syndecan‐1 could be a useful marker of malignant transformation in the lip.