Retinoic acid (RA) induces proliferation arrest, differentiation, and apoptosis, and defects in retinoic acid receptor (RAR) signaling have been implicated in cancer. The human tumor antigen PRAME is overexpressed in a variety of cancers, but its function has remained unclear. We identify here PRAME as a dominant repressor of RAR signaling. PRAME binds to RAR in the presence of RA, preventing ligand-induced receptor activation and target gene transcription through recruitment of Polycomb proteins. PRAME is present at RAR target promoters and inhibits RA-induced differentiation, growth arrest, and apoptosis. Conversely, knockdown of PRAME expression by RNA interference in RA-resistant human melanoma restores RAR signaling and reinstates sensitivity to the antiproliferative effects of RA in vitro and in vivo. Our data suggest that overexpression of PRAME frequently observed in human cancers confers growth or survival advantages by antagonizing RAR signaling.