The unique ability of the vanadyl pyrophosphate (1 0 0) surface to activate n-butane and then selectively oxidise the hydrocarbon to maleic anhydride was investigated using modern quantum chemical methods. Bulk (VO)2P2O7, together with stoichiometric and phosphorus-enriched (1 0 0) surfaces, were analysed using periodic density functional theory calculations. Also simulated was surface ionic relaxation from bulk geometry, and surface hydration. Density of states (DOS) plots show that, whether stoichiometric or phosphorus-enriched, bulk terminated or relaxed, bare or hydrated, local covalent reactivity at the (1 0 0) surface is controlled by vanadium species. Terminal P–O oxygen species are the most nucleophilic surface oxygens, as indicated by their predominance of sub-vanadium high-lying valence band levels. A periodic treatment of (VO)2P2O7(1 0 0) hence gives results qualitatively identical to those obtained from earlier cluster calculations. Simulation of surface ionic relaxation shows that in-plane P–O–V oxygens may also be involved in rupture of substrate C–H bonds for mild oxidation, while surface hydration calculations indicate that dissociative chemisorption of water may play a key role in perpetuation of the selective oxidation cycle.