Retinoids are natural and synthetic analogues of vitamin A and have proven activity in various types of cancer. As for head and neck squamous cell cancer (HNSCC), retinoids are especially active in leukoplakia and in preventing second primary cancers. The aim of this study was to assess the growth inhibiting activity of all-trans retinoic acid (all-trans RA) in a panel of six head and neck squamous cell cancer cell lines and to correlate this response to the mRNA expression of factors related to differentiation and receptor mediated signal transduction. Three lines showed minimal, two moderate and one strong growth inhibition after 72 h exposure to all-trans RA. Three lines with a dissimilar response were selected for further studies, the measurement of mRNA expression by northern blotting. It was found that neither the expression nor the induction of retinoic acid receptor (RAR) -α and -γ and retinoic X receptor-α mRNA was related to sensitivity. The mRNA expression of RAR-β was too low to be measured in the three cell lines. The most sensitive cell line was, however, the only one that expressed mRNA of squamous differentiation markers. These data suggest a relationship between the retinoid sensitivity profile and the degree of cellular differentiation.