The retinoic acid receptor (RAR) is a retinoic acid (RA)-inducible tumor suppressor, which plays an important role in the arrest of neuroblastoma cell growth. Using human neuroblastoma SH-SY5Y cells we have examined the regulation of RAR expression by histone deacetylase inhibitors (HDACi), considered to be promising agents in anti-cancer therapy. Our results show that HDACi cooperated with RA to increase RAR mRNA levels and to activate the RAR2 promoter in transient transfection assays. Chromatin immunoprecipitation assays showed that the basal RAR2 promoter that contains the RA response element was refractory to acetylation by both HDACi and RA. In addition, HDACi caused a transient increase in acetylation of a downstream RAR2 region, even though global histones remain hyperacetylated after a prolonged treatment with the inhibitors. RA potentiated this response and maintained acetylation for a longer period. Despite the cooperation of RA with HDACi to increase transcription of the RAR gene, these inhibitors caused a paradoxical reduction of the cellular levels of the RAR protein in cells treated with the retinoid. This reduction is secondary to a change in the protein half-life that is decreased by the HDACi due to increased ubiquitin-independent proteasomal degradation. These results show that HDACi regulate expression of the tumor suppressor gene RAR by both transcriptional and post-transcriptional mechanisms, and might then modulate sensitivity to the retinoid in neuroblastoma cells.