SYF2 is thought to be a cell cycle regulator at the G1/S transition, which encodes a nuclear protein that interacts with cyclin D-type binding-protein 1. In the present study, we investigated the role of SYF2 in human glioma progression. Immunohistochemical and Western blot analyses were performed in human glioma tissues. High SYF2 expression (located in cell nuclei) was observed in 80 samples, and its level was correlated with the grade of malignancy. A strongly positive correlation was observed between SYF2 and Ki-67 expression (P < 0.01). More importantly, high expression of SYF2 was associated with a poor outcome. In vitro, after the release of U87 cell lines from serum starvation, the expression of SYF2 was upregulated, as well as PCNA and cyclin D1. In addition, knockdown of SYF2 by small interfering RNA transfection diminished the expression of PCNA, cyclin D1 and arrested cell growth at G1 phase. These results indicate that SYF2 in glioma is essential for cell proliferation; thus, targeting SYF2 or its downstream targets may lead to novel therapies for glioblastomas.