By choosing the cryogenic distillation column cascade developed at Los Alamos National Laboratory, the effects of helium on separation characteristics of the columns are analyzed in a probable case of input and output specifications. Column (2) is mainly affected by the presence of helium. If the helium percentage in the raw fuel input is 1%, the column performance can be assured by increasing the condenser load. No special helium separator may be needed, but a larger inner diameter of the column, larger flow rate of the refrigerant gas, and larger heat transfer area at the condenser should be considered in the design stage. If the percentage is 5%, both the column pressure and condenser load must be doubled in the steady-state operation. The control operation for the tritium level in the top gas is unavoidably accompanied by a remarkable decrease in the condenser temperature; thus, the controls of the pressure and liquid level in the reboiler are greatly vitiated. If the percentage is 10%, the column must be operated at ∼4 atm, and even the steady state requires a three times heavier condenser load and an ∼25% increase in the packed height. Considering the remarkable effects of helium on the control operation for column (2), the helium removal should be completed before feeding hydrogen isotopes to the column cascade if the helium percentage has a significant value (>1%).