Structural phase transitions of N2-loaded and guest-free hydroquinone (HQ) clathrates have been investigated as a function of pressure using synchrotron X-ray diffraction and Raman spectroscopy. The N2-loaded β-form HQ clathrate reveals a structural transition to a new high pressure phase near 4 GPa and exhibits gradual N2 release from the hydrogen-bonded organic framework (HOF) cage with a further increase in pressure. Upon reducing the pressure to ambient conditions, the crystal structure reverts to the original β-form HQ clathrate, indicating that the pressure-induced structural transition is fully reversible. In contrast, around 0.4 GPa, the guest-free β-form HQ clathrate undergoes an irreversible phase transition to the nonporous α-form HQ, which is retained at ambient conditions. These results suggest that HOF encaged guest molecules play an important role in the structural transitions under high pressure.