Peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated transcription factor. PPARα regulates lipid and glucose metabolism and controls the inflammatory response. Recently, we have shown that PPARα is a short-lived protein degraded by the ubiquitin–proteasome system. In this study, we have analysed the effects of interaction with RXRα, CBP, and N-CoR and also the implication of phosphorylation on ubiquitination and stability of PPARα. Our results show that interaction of PPARα with RXRα or CBP leads to an increase in the turnover of the protein. In contrast, interaction with the corepressor N-CoR, which inhibits its transcriptional activity, leads to a stabilization of the protein. Interestingly, treatment of cells with an inhibitor of Ser/Thr phosphatases known to lead to hyperphosphorylation of PPARα induces its transcriptional activity which is accompanied by a stabilization of the protein. These data indicate that heterodimerization, recruitment of cofactors, and post-translational modifications can modulate the stability of PPARα.