Three high-pressure phases of trimethylacetonitrile, a compound of potential interest in the context of Titan's atmospheric chemistry, have been investigated using single-crystal X-ray diffraction, periodic density functional theory, and CrystalExplorer intermolecular energy calculations. A disordered tetragonal P4/nmm phase is formed between 0.07 and 0.29 GPa (denoted hp-I). Compression to 0.43 GPa forms an ordered orthorhombic Pnma phase (hp-II), which transforms to a monoclinic P2 1 /m phase (hp-III) at 1.52 GPa. The hp-III phase persists to at least 3.34 GPa. Phase transitions are driven by densification of the crystal and facilitated by rearrangement of the supramolecular hydrogen-bonding network, with 180°reorientation of half the molecules. Compression of each phase is associated with slight shortening of the intermolecular hydrogen bonds, with gradual destabilization of the cohesive energy to 3.34 GPa.