Cleavage of the labile halide termination upon matrix-assisted laser desorption/ionization (MALDI) has always been reported as a major concern in mass analysis of polystyrene prepared by atom transfer radical polymerization (ATRP). By studying this issue using nuclear magnetic resonance (NMR) and electrospray ionization-mass spectrometry, we evidence here that the ionization step is not involved in this deleterious process. Instead, removal of the halogen was shown to readily occur upon interaction of the silver salt (AgTFA) used as the cationizing agent in mass spectrometry, either in solution or in the solid-state when performing solvent-free sample preparation. In solution, this silver-induced reaction mostly consists of a nucleophilic substitution, leading to polystyrene molecules holding different terminations, depending on relative nucleophilicity of species present in the liquid-phase solution composition. In chloroform supplemented with AgTFA, trifluoroacetate-terminated PS were evidenced in ESI-MS spectra but experienced end-group cleavage in MALDI. In contrast, the major methoxy-terminated PS macromolecules formed when the silver-catalyzed nucleophilic substitution was performed in methanol were generated as intact gas-phase ions using both ionization techniques. This controlled and fast modification could hence be advantageously used as a rapid sample pretreatment for safe MALDI mass analysis of ATRP-made polystyrene.