Since vitamin A inhibits the terminal differentiation of keratinocytes, elevated levels of cytoplasmic vitamin A-binding proteins could explain the reduced tendency of squamous cell carcinomas to undergo terminal differentiation. The levels of cellular retinol-binding protein (CRBP) and cellular retinoic acid-binding protein (CRABP) were determined in 37 squamous cell carcinomas of the head and neck and were compared with the corresponding levels in adjacent normal tissue. The CRBP levels expressed per milligram of DNA were increased threefold (P = 0.0005) in the tumor as compared with normal tissue. In contrast, CRABP levels expressed per milligram were decreased 2.5-fold (P = 0.0007) in the tumor as compared with normal tissue. Despite significant differences in retinoid-binding protein levels between tumor and adjacent normal tissue, there was no significant correlation of these differences with any of the patient clinical parameters or any of the tumor growth characteristics. The increased CRBP levels may explain why terminal differentiation, an important mechanism for limiting growth in normal keratinocytes, is less readily induced in squamous cell carcinomas.