The efficient formation of HCN/HNC from formamide (FM) combining the advantages of water-assistance, self-catalyzed reactions, and the mineral surfaces was investigated. Periodic density functional theory calculations with plane-wave pseudopotential basis sets were performed to study the interaction of FM with pyrite (100) ideal and defect surfaces. Effects of sulfur vacancy defect and water on tautomerization and rearrangement barriers of FM on the (100) surface were evaluated. Calculated results show that FM adsorbs more strongly on the defect surface than on the ideal surface, with the lowest adsorption energy on the defect surface being -22 kcal/mol. The energy barriers for rearrangements of FM on these two surfaces being close to each other suggests that the adsorptions on the surfaces have small effects on the energy barriers. The energy barriers for formimic acid isomer formations are 44.5 and 46.0 kcal/mol, and those of aminohydroxymethylene formations are 72.6 and 71.9 kcal/mol on the ideal and defect surfaces, respectively. A reduction of similar to 30 kcal/mol in tautomerization energy barriers is observed in water-assisted process on the defect surface. Because this reduction is close to that of the gas-phase reactions, the catalytic effect is clearly due to the presence of water molecule instead of the interaction with the surface. In this case, the pyrite surfaces with the ability to accumulate reactive species only play the role of connecting bridges between the two steps of the proposed reaction mechanism: the water-assisted rearrangement and the self-catalyzed dehydration.