Although vast experimental experience has been accumulated about the reactions of icosahedral B12H122- borane cages, little is known about the mechanisms by which these reactions proceed. To address this issue, we have chosen the thiocyanation of B12H122- and have studied this reaction using both experimental and theoretical methods. First, we present a novel and more convenient synthetic route using in situ generated thiocyanogen, (SCN)(2). The synthesized disubstituted product B12H10(SCN)(2)(2-) is exclusively the meta positional isomer, as confirmed by the X-ray crystallographic analysis. The quantum chemical calculations at the B3LYP/def2-TZVP//RI-PBE/def2-SVP level show that the free energy differences between the ortho, meta, and para disubstituted species are very small and as such cannot explain the observed positional preferences. The calculations of the kinetic aspects reveal that the reaction is best described as an electrophilic substitution. The calculated isomer preferences for the second SON substituent are meta > para > ortho. The major outcome of this work is a clear and consistent picture of the electrophilic substitution reaction mechanism of the thiocyanation of B12H122-, thus contributing to our understanding of the general features of boron hydride reactivity.