Reactive molecular dynamics simulations of Ti3C2Tx layers with three different surface terminations were used to understand friction and failure of MXenes during sliding. O-terminated MXenes had the smallest shear stress at low pressures and temperatures, but failed at more severe conditions due to interlayer bonding and the formation of Ti-O-Ti bridges between the MXene layers. Failure was not observed for the OH-terminated MXene or a heterostructure that combined O- and OH-terminated layers. At less severe operating conditions, shear stress was smaller for the OH-terminated MXene, while the opposite was observed at higher temperatures and pressures. These trends were explained in terms of adhesion and the complex effect of hydrogen atoms that can either facilitate or hinder sliding, depending on the termination and conditions. Results show that friction and failure are affected by and potentially tunable via MXene surface termination.