The synthetic retinoid 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid (CD437) induces apoptosis in a variety of cancer cells including lung cancer cells. Our previous studies have demonstrated that cancer cells with wild-type p53 are more sensitive to CD437 than those having mutant p53, although CD437 can induce both p53-dependent and -independent apoptosis. Because normal human lung epithelial cells have wild-type p53, the question arose as to whether they are also sensitive to CD437-induced apoptosis. To address this question, we compared and contrasted the effects of CD437 on apoptosis induction and the expression of several p53-regulated apoptosis-related genes between normal human lung epithelial cells and human lung cancer cells containing wild-type p53. CD437 induced apoptosis as evidenced by apoptotic morphological changes, increased DNA fragmentation, and activation of caspase cascades in two lung cancer cell lines but not in two normal human lung epithelial cells. CD437 selectively increased the p53 protein level and concomitantly induced the expression of several p53-regulated apoptosis-related genes including Bax, Fas, DR4, and DR5 only in the two lung cancer cell lines. Furthermore, the normal lung epithelial cells, which expressed constitutively higher levels of two antiapoptotic decoy receptors DcR1 and DcR2 than lung cancer cells, exhibited an increase in the expression of these receptors after CD437 treatment, whereas no increase was detected in lung cancer cells. These results predict a differential effect of CD437 on tumor and normal cells in vivo and strongly suggest that CD437 may be a useful agent for chemoprevention and/or treatment of human cancer, especially lung cancer.