Increasing evidence indicates that Liver X Receptors (LXRs) have some anticancer properties. We recently demonstrated that LXR ligands induce colon cancer cell pyroptosis through an LXRbeta-dependent pathway. In the present study, we showed that human colon cancer cell lines presented differential cytoplasmic localizations of LXRbeta. This localization correlated with caspase-1 activation and cell death induction under treatment with LXR ligand. The association of LXRbeta with the truncated form of RXRalpha (t-RXRalpha) was responsible for the sequestration of LXRbeta in the cytoplasm in colon cancer cells. Moreover t-RXRalpha was not expressed in normal colon epithelial cells. These cells presented a predominantly nuclear localization of LXRbeta and were resistant to LXR ligand cytotoxicity. Our results showed that predominant cytoplasmic localization of LXRbeta, which occurs in colon cancer cells but not in normal colon epithelial cells, allowed LXR ligand-induced pyroptosis. This study strengthens the hypothesis that LXRbeta could be a promising target in cancer therapy.