Pirh2, a p53-induced ubiquitin-protein ligase, has been reported to promote ubiquitin-dependent degradation of p27(kip1), which plays an essential role in mammalian cell cycle regulation and neurogenesis in the developing central nervous system (CNS). However, their distributions and functions in the nervous system lesion and repair remain unclear. In this study, we observed that the up-regulated expression of Pirh2 was concomitant with decreased p27(kip1) level after traumatic brain injury by Western blot and immunohistochemistry. Immunofluorescence double-labeling revealed that Pirh2 was mainly co-expressed with GFAP and CD11b. Meanwhile, we also examined the expression profiles of proliferating cell nuclear antigen (PCNA) whose changes were correlated with the expression of Pirh2. In addition, Pirh2 colocalized with p27(kip1) and PCNA. Immunoprecipitation further showed that they interacted with each other in the pathophysiology process. In summary, our data indicated Pirh2 might be a negative regulator of p27(kip1) and associated with glial proliferation.