PP2Cgamma is a splicing factor that dephosphorylates specific substrates required for the formation of the spliceosome. In a previous study, we reported that the degradation of p21(Cip1/WAF1)was affected by PP2Cgamma, causing an accumulation of cells in S phase. Here, we demonstrate that the PP2Cgamma-induced degradation of p21(Cip1/WAF1) is mediated by Akt signaling. In cells expressing PP2Cgamma, Akt1 protein was phosphorylated. When PP2Cgamma expression was knocked down, the phosphorylation of Akt1 was reduced and the level of p21(Cip1/WAF1) protein was increased. Interestingly, the stability of p21(Cip1/WAF1) was highly maintained in Akt1-depleted cells despite the ectopic expression of PP2Cgamma. Taken together, these results suggest that PP2Cgamma is a novel regulator of p21(Cip1/WAF1) protein stability via the Akt signaling pathway.