We studied the reaction between aquacobalamin (H2OCbl) and selenocysteine (Sec), a selenium‐containing analogue of cysteine, using conventional UV/Vis spectroscopy. This reaction leads to the formation of cob(II)alamin [Cbl(II)] without any detectable intermediate complexation of Cbl(III) with selenocysteine, whereas the interaction between H2OCbl and cysteine proceeds distinctly through the coordination of Cys onto the CoIII ion with further reduction of the CoIII–Cys complex to Cbl(II). The latter is slower than the reaction with Sec. We also showed that selenocystine is capable of accelerating the reduction of H2OCbl to Cbl(II) by cysteine.