The corrosion of Hastelloy C-22 at room temperature in acetonitrile (MeCN) solutions containing various concentrations of tetrabutylammonium chloride (Bu4NCl), HCl and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) was investigated, mimicking aggressive environments used in the synthesis of pharmaceuticals. In the absence of sources of Cl–, C-22 is passive in MeCN. In neutral MeCN containing Bu4NCl, C-22 undergoes pitting upon anodic polarization. C-22 presents an active-passive transition in MeCN with 5 mM HCl. In HCl concentrations above 5 mM, C-22 is completely active and icorr increases with HCl concentration. Comparing with the literature in aqueous corrosion of C-22, the breakdown of passivity in MeCN takes place at much lower chloride additions. The corrosion in MeCN/HCl/DDQ solutions can achieve surprisingly high rates, as seen in electrochemical tests (icorr = 6.5 mA cm−2) and mass loss tests (penetration rate > 10 mm y−1), due to the oxidizing power of DDQ. In equimolar concentration, HCl and DDQ have a synergistic effect on the elevation of the cathodic kinetics of C-22 corrosion, due to the effects of acidity on the reduction of DDQ.