Clinoenstatite (Mg2Si2O6) undergoes a well-known phase transition from a low-pressure form (LPCEN, space group P21/c) to a high-pressure form (HPCEN, space group C2/c) at ~6 GPa. High-pressure structure refinements of HPCEN were carried out based on single-crystal X-ray diffraction experiments between 9.5 and 35.5 GPa to determine its P-V equation of state and structural evolution over an expanded pressure range relevant to pyroxene metastability. The best-fit isothermal equation of state to our data combined with the five data points between 5.34 and 7.93 GPa from Angel and Hugh-Jones (1994) yields a second-order Birch-Murnaghan equation with KT0 = 121(2) GPa and V0 = 403.9(5) Å3 (with = 4 implied). Further reduction of misfit upon fitting a third-order Birch-Murnaghan equation is not significant at the 90% confidence level. At ~45 GPa, a transition from HPCEN to a P21/c-structured polymorph (HPCEN2) was observed, which is isostructural to the P21/c phase recently observed in diopside (CaMgSi2O6) at 50 GPa (Plonka et al. 2012) and in clinoferrosilite (Fe2Si2O6) at 30–36 GPa (Pakhomova et al. 2017). Observation of HPCEN2 in Mg2Si2O6 completes the third apex of the pyroxene quadrilateral wherein HPCEN2 is found, facilitating a broader view of clinopyroxene crystal chemistry at conditions relevant to metastability in the Earth’s mantle along cold subduction geotherms.