Carbon isotopes are widely used in numerous industries, especially in medicine. The advantage of using C-13-labeled products is only shadowed by the difficulty of increasing the natural concentration. One method available is a train of cryogenic distillation columns. This paper presents a preliminary analysis of three different control strategies for a unit comprising three 7-m-high isotope separation columns: a decentralized multivariable proportional-integral controller and two decoupling control algorithms. For the first one, a single controller is designed for the entire distillation column train, whereas for the second decoupling approach, three separate controllers are designed for each of the three columns. Simulation results show that the last approach provides significantly improved results when compared to the other two control strategies.