Abstract: Calculations of traditional HF and DFT based reactivity descriptors are reported for the benzofused thieno[3,2-b]furans in order to get insight into the factors determining the exact nature of its interactions with electrophiles. Global descriptors such as chemical potential, molecular hardness, electrophilicity, frontier molecular orbital energies and shapes, the condensed Fukui functions were determined and used to identify the differences in the stability and reactivity of heterocycles. In general calculated values lead to the conclusion that heterocyclic system in thieno[3,2-b]benzofuran is more aromatic and stable than in isomeric benzothieno[3,2-b]furan. Theoretical results are in complete agreement with the experimental results showing exceptional reactivity of C(2) atom for both isomers. The bond order uniformity analysis, local ionization energy and electrostatic potential energy maps revealed structural and reactivity differences of isomeric thieno[3,2-b]furans. Benzothieno[3,2-b]furan structurally could be analogues with molecule of aromatic benzothiophene substituted with C(2)-C(3) vinylic moiety. Contrary, calculated values for the of thieno[3,2-b]benzofuran shows delocalized p–electron surface that reports stable aromatic system between benzene ring and thiene heterocycle. This evidently point out wherefore the electrophilic substitution reaction for benzothieno[3,2-b]furan goes via addition-elimination mechanism at the C(2) position, and presumes possibility of aromatic electrophilic substitution mechanism scenario for thieno[3,2-b]benzofuran.