Liver X receptors (LXRs) α and β are ligand-induced transcription factors that regulate transcription of genes encoding key regulators of cholesterol metabolism and transport, and of lipogenesis. Despite their high similarity, LXRα is the functionally dominant LXR isotype in the liver. The function of nuclear proteins can be affected by their sequestration in the nucleoli. Whereas most nuclear receptors are excluded from the nucleolus, some are not. To explore nucleolar exclusion of LXRα and LXRβ, we used cells expressing cyan fluorescent protein (CFP) chimeras with LXRα (CFP-LXRα) and wild-type and mutant CFP-LXRβ and marked the nucleolus with anti-fibrillarin antibody. Significantly more CFP-LXRβ than CFP-LXRα in the nucleoli. Mutations in basic-rich sequences in the DNA binding domain caused some exclusion of CFP-LXRβ from the nucleolus. Moreover, mutations in the activation function-2, an important protein–protein interaction site in all nuclear receptors, resulted in exclusion of CFP-LXRβ from the nucleolus. These data suggest protein–protein interactions that may regulate nucleolar sequestration of LXRβ.