Carcinogenesis is considered a multistep process. To further elucidate involved genetic changes, the differential display method was applied to compare gene expression of head and neck carcinoma cells and normal keratinocytes from the upper aerodigestive tract. Total RNA was extracted from cultured squamous carcinoma cells and keratinocytes. mRNA was reverse transcribed into cDNA, amplified by PCR, and separated on a gel. Currently three DNA transcripts were identified with a length of 191 to 336 base pairs (bp) that were either expressed only by the keratinocytes or by the malignant cells. Differentially expressed DNA fragments of the carcinoma cells and the keratinocytes were cloned and sequenced. A gene bank database search identified one fragment expressed by the carcinoma cells as an unknown gene, another one found in the keratinocytes as probably a part of the human cell attachment domain, and the third one with homology to the mRNA of the human epidermal growth factor receptor (EGFR). Northern blot analysis confirmed the differential expression in the malignant cells or the keratinocytes. Differential display seems to confirm the well-known overexpression and up-regulation of the EGFR, the differential expression of the cell attachment domain may play a role as a cofactor in carcinogenesis of head and neck cancer, and the third unknown fragment is still under investigation to elucidate the role in carcinogenesis.