We report a reversal in the isotopic dependence of energy confinement with increasing system size from electrostatic global δf gyrokinetic simulations. The favorable isotope effects on the energy confinement observed in past and present-day tokamaks may diminish or reverse in future tokamaks with significantly larger . This finding offers critical insights for the design of future tokamaks, such as ITER, DEMO and fusion plants, particularly those with larger sizes or stronger magnetic fields. The primary mechanism driving this reversal is the isotope mass dependence of the turbulence radial correlation length, which is significantly weaker than Bohm scaling at low and closer to gyro-Bohm scaling at high .