Although there does not exist simultaneously the optimal angle of inclination and optimal plate spacing for maximum separation of heavy water from water–isotope mixture in flat-plate thermal-diffusion columns, increasing either inclination angle or plate spacing will increase, respectively, the optimal plate spacing or optimal inclined angle, as well as the corresponding maximum separations. The equations for the optimal angle of inclination and optimal plate spacing, as well as the corresponding maximum separations, have been derived. Considerable improvement in separation is achievable if the operations are conducted with the optimal conditions.