We investigate fast, highly charged ion-induced HOD molecule fragmentation dynamics. Focusing on double ionization of the molecule, we evidence a strong preferential cleavage of the O–H bond rather than the O–D bond. We find an isotopic branching ratio defined as the number of H+ + OD+ over D+ + OH+ dissociations of 6.5 ± 0.5. Moreover, the coincident measurement, by imaging techniques, of high-resolution kinetic energy release (KER) distributions for different fragmentation channels shows, for the first time, a clear difference of approximately 1 eV between the mean KER value of the two-body dication fragmentation channels H+ + OD+ and D+ + OH+. We analyse the two aspects of this isotopic effect by means of a semi-classical calculation simulating the dissociation dynamics via the dication electronic ground state. The final pathway is found to be strongly correlated to the initial position and momentum distributions. Those correlations explain both the observed O–H bond preferential cleavage and, for a large part, the different mean KER values. The other part of the 1 eV kinetic energy difference results from different vibrational energies of the residual molecular fragment that have also been estimated.