Despite fast protein degradation in muscles, protein concentrations remain constant during differentiation and maintenance of muscle tissues. Myogenin, a basic helix-loop-helix-type myogenic transcription factor, plays a critical role through transcriptional activation in myogenesis as well as muscle maintenance. TBP-interacting protein 120/cullin-associated neddylation-dissociated (TIP120/CAND) is known to bind to cullin and negatively regulate SCF (Skp1-Cullin1-F-box protein) ubiquitin ligase, although its physiological role has not been elucidated. We have identified a muscle-specific isoform of TIP120, named TIP120B/CAND2. In this study, we found that TIP120B is not only induced in association with myogenic differentiation but also actively accelerates the myogenic differentiation of C2C12 cells. Although myogenin is a short lived protein and is degraded by a ubiquitin-proteasome system, TIP120B suppressed its ubiquitination and subsequent degradation of myogenin. TIP120B bound to cullin family proteins, especially Cullin 1 (CUL1), and was associated with SCF complex in cells. It was demonstrated that myogenin was also associated with SCF and that CUL1 small interference RNA treatment inhibited ubiquitination of myogenin and stabilized it. TIP120B was found to break down the SCF-myogenin complex. Consequently suppression of SCF-dependent ubiquitination of myogenin by TIP120B, which leads to stabilization of myogenin, can account for the TIP120B-directed accelerated differentiation of C2C12 cells. TIP120B is proposed to be a novel regulator for myogenesis.