In the last decades a lot of efforts were dedicated to the individuation of small size selenium containing molecules able to mimic the catalytic activity of the Glutathione Peroxidase (GPx). A number of tests were adopted to evaluate by UV, HPLC, NMR the ability of an organoselenium compound on reducing hydrogen peroxide in the presence of a thiol cofactor. Based on these tests a plethora of different compounds were claimed as GPx-mimetics even if, right now, no one of these compounds confirmed the excellent in vitro results when it was translated in cells or animal, and usually the most frustrating issue is the toxicity. In addition the panel of different analytical tests used to measure the GPx-like activity, including a series of different thiol cofactors, in many cases do not allow the direct comparison of the presented activity of different classes of compounds neither the real comprehension of the current mechanism in the biological environment. When DTT is used as cofactor the regeneration of the catalyst occurs thought an intramolecular thiol oxidation that have a different kinetic respect to the naturally occurring oxidation of the glutathione that is an intermolecular process. Here we also demonstrate that DMSO, used as solvent or co-solvent in a redox biological test in the presence of a selenium catalyst, could act as a co-factor in the reduction of the peroxide introducing an unpredictable and unavoidable bias that will affect any kind of analytical evaluation. Antioxidant or prooxidant that’s the problem