Retinoids mediate their actions via retinoic acid receptors (RARs) and retinoid X receptors (RXRs). Each of class of these nuclear retinoid receptor is further subdivided into three species namely alpha, beta and gamma. Recently studies demonstrated that estrogen receptor (ER)-positive human breast cancer (HBC) cell lines are sensitive and ER-negative cell lines are resistant to growth inhibitory effects of retinoic acid (RA). In this study, we found that only RAR alpha mRNA levels was strongly correlated with ER-status. To further investigate the major role of RAR alpha in retinoid-mediated inhibition of growth, we transfected RAR alpha cDNA into two RA-resistant ER-negative HBC cell lines. Analysis of different clonal populations of RAR alpha transfectants from each cell line revealed growth inhibition by retinoids. Our results demonstrated that RAR alpha plays a major role in mediating retinoids inhibition of growth in HBC cells and adequate levels of RAR alpha are required for such an effect.