To study the tissue-specific expression of neu oncogene, we used two mouse tumor cell lines derived from liver, Hep1-a, and pancreatic, 266-6, tumors as a model system. The endogenous neu gene is expressed in Hep1-a but not in 266-6 cells. We demonstrate in this report that differential expression of the neu gene in these two cell lines is mainly regulated at transcriptional level. The neu promoter sequence responsible for the differential regulation is localized within a 90 bp region and it is possibly due to lack of a specific positive transcription factor(s) interacting with this region in 266-6 cells.