Arsenite trioxide (As 2 O 3) induces apoptosis in several cell lines by disturbing key signal transduction pathways through its oxidative properties. Here, we report that As 2 O 3 also induces the phosphorylation of the retinoid receptor RXRα, subsequent to oxidative damages and the activation of the stress-activated protein kinases cascade (JNKs). We also report that RA amplifies both As 2 O 3-induced phosphorylation of RXRα and apoptosis. Taking advantage of ‘rescue’F9 cell lines expressing RXRα mutated at its phosphorylation sites, in an RXRα null background, we provide evidence that RXRα is a key element involved in that potentiating effect. Finally, we demonstrate that As 2 O 3 also abrogates the transactivation of RA-target genes.