We present the origin of the observed differentiation of lactose and lactulose achieved by complexation with sodiated l -arginine (ArgNa + ). We find that the infrared multiphoton dissociation (IRMPD) bands in 3600–3650 and >3650 cm −1 regimes for gas phase lactose and lactulose, respectively, vanish when forming host–guest complexes with ArgNa + . We interpret these differences in the IRMPD spectra by scrutinizing the interactions between the functional groups (guanidium, –CO 2 − Na + ) in ArgNa + and –OHs in lactose/lactulose. Our calculated structures and infrared spectra of lactose/ArgNa + and lactulose/ArgNa + host–guest pairs indicate that the functional groups interact with the low- and high-frequency –OH stretch modes of lactose and lactulose, respectively, in the 3600–3720 cm −1 window.