OBJECTIVE: The present study was conducted to evaluate the levels of Cdk2, cyclin E, p21, and p27 in growth hormone adenomas (GHPAs) and analyze their association with clinicopathologic features. METHODS: We collected 46 GHPA specimens and clinical materials from March 2012 to December 2015 at Beijing Tiantan Hospital. We analyzed the expression of Cdk2, cyclin E, p21, and p27 using immunohistochemistry, quantitative real-time polymerase chain reaction, Western blot, and methylation-specific polymerase chain reaction and sequencing. RESULTS: The levels of cyclin E and Cdk2 were much greater in the invasive group than in the noninvasive group (P < 0.05). Significant differences were found between cyclin E and p21 and tumor size (P < 0.05) and between cyclin E expression and invasion (P < 0.05). Tumors were more likely to require whole resection in patients with low cyclin E expression (P < 0.05). The high-level p27 group had better progression-free survival than did the low-level p27 group (P < 0.01). Quantitative real-time polymerase chain reaction and Western blot analysis revealed a similar trend for Cdk2, cyclin E, p21, and p27 protein levels in growth hormone specimens (P < 0.01). An average of 33 CpG sites per sample were analyzed using matrix-assisted laser desorption ionization time-of-flight mass array, and in 7 of the 33 CpG sites, the methylation levels of p27 were > 50%. Statistically significant differences were found in 4 CpG sites between the invasive and noninvasive specimens (P < 0.01). CONCLUSIONS: Overexpression of cyclin E/Cdk2 and loss of p27 appears to be associated with a poor prognosis and might play a role in the treatment of GHPAs in the future.