We report the results of high-level ab initio calculations for the gas-phase interconversion of azido and tetrazole forms of thiazole[3,2-d]tetrazole. This study is supplemented with an analysis of the solvent effect on the isomerism using self-consistent reaction field (SCRF) and Monte Carlo-Free Energy Perturbation (MC-FEP) techniques in three different solvents:  carbon tetrachloride, chloroform, and water. Finally, the influence exerted by the introduction of substituents on the relative population of isomers is also examined. The energy difference between azido and tetrazole species is found to be highly sensitive to the level of theory used to describe the gas-phase reaction. It also found that the free energies of solvation of azido and tetrazole species determined from SCRF or MC-FEP calculations allow us to predict the solvent-induced changes on the equilibrium. The results show that the azido form of thiazole[3,2-d]tetrazole is clearly disfavored as the solvent polarity increases. The influence played by substituents is also consistent with the experimental available data, it being shown that electron-withdrawing groups favor the azido isomer, while the opposite effect is observed for electron-donating substituents. The study demonstrates the capability of high-level quantum mechanical calculations combined with SCRF or MC-FEP results to analyze the azido−tetrazole isomerism and its dependence on the solvent and substituents.