Tumors show an increased glucose uptake that is mediated by glucose transport proteins. We have analyzed the expression of the sodium-dependent glucose co-transporters SGLT-1 and-2 in short-term cultures of squamous cell carcinomas of the head and neck (HNSCC) by RT-PCR. Distribution of the SGLT-1 protein in HNSCC tissues was investigated by immunohistochemistry. While we observed in 17/36 HNSCC short-term cultures the SGLT-1 mRNA, we found no SGLT-2 expression. SGLT-1 mRNA expression occurred preferentially in cultures originating from moderately and well differentiated HNSCC. In tumor tissues a heterogeneous SGLT-1 staining restricted to differentiated tumor cells was seen in 27/30 HNSCC analyzed. In normal mucosa SGLT-1 staining was also confined to differentiated compartments and lacked in dysplastic areas. Our data indicate a differentiation-dependent expression of SGLT-1 in HNSCC. This is important knowledge for the planning of glucose-targeting therapies and suggest SGLT-1 as a differentiation marker in head and neck tissues.