Hypochlorous　acid　(HOCl)　released　from　activated　leukocytes　not　only　plays　a　significant　role　in　the　human　immune　system　but　is　also　implicated　in　numerous　diseases　including　atherosclerosis　and　some　cancers　due　to　its　inappropriate　production.　Histidine　(His)　and　carnosine　(Car),　as　a　respective　mediator　and　protective　agent　of　HOCl　damage,　have　attracted　considerable　attention;　however,　their　detailed　reaction　mechanisms　are　still　unclear.　In　this　study,　using　a　His　residue　with　two　peptide　bond　groups　(HisRes)　as　a　model,　the　reaction　mechanisms　of　HisRes　and　Car　including　N　epsilon　H　and　N　delta　H　tautomers　with　HOCl　along　with　the　chlorination　reactivity　of　N-chlorinated　intermediates　were　investigated　by　quantum　chemical　methods.　The　obtained　results　indicate　that　in　the　imidazole　side　chain,　the　pyridine-like　N　is　the　most　reactive　site　rather　than　the　pyrrole-like　N,　and　the　kinetic　order　of　all　of　the　possible　reaction　sites　in　HisRes　follows　pyridine-like　N　＞　imidazole　C-delta　＞＞　imidazole　C-epsilon　＞　pyrrole-like　N,　while　that　in　Car　is　pyridine-like　N　＞＞　imidazole　C-delta　＞＞　amide　N.　As　for　N-chlorinated　intermediates　at　imidazole,　although　the　unprotonated　form　has　a　low　chlorination　reactivity　as　expected,　it　can　still　chlorinate　tyrosine.　Especially,　the　protonated　form　exhibits　similar　ability　to　HOCl,　causing　secondary　damage　in　vivo.　N-Chlorinated　Car　features　higher　internal　chlorine　migration　ability　than　its　intermolecular　transchlorination,　preventing　further　HOCl-induced　damage.　Additionally,　a　generally　overlooked　nucleophilic　Cl-　shift　is　also　found　in　N-chlorinated　Car/HisRes,　indicating　that　nucleophilic　sites　in　biomolecules　also　need　to　be　considered.　The　outcomes　of　this　study　are　expected　to　expand　our　understanding　of　secondary　damage　and　protective　mechanisms　involved　in　HOCl　in　humans.