The crystal structure of paliperidone has been solved and refined using synchrotron X-ray powder diffraction data, and optimized using density functional techniques. Paliperidone crystallizes in space group P21/n (# 14) with a = 14.151 58(6), b = 21.537 80(9), c = 6.913 26(2) Å, β = 92.3176(2)°, V = 2105.396(13) Å3, and Z = 4. The unit-cell volume at 295 K is 1.5% larger than at 200 K, but the expansion is anisotropic; the b-axis is nearly constant at the two temperatures, while the a- and c-axes expand by 0.71 and 0.87%, respectively. There is only one significant hydrogen (H)-bond in the crystal structure. This H-bond is between the hydroxyl group O31–H58 and the ketone oxygen O25. The result is a chain along the c-axis with graph set C1,1(7). In addition to this H-bond, the molecular packing is dominated by van der Waals attractions. The powder pattern is included in the Powder Diffraction File™ as entry 00-064-1497.