Deuterium and oxygen-18 isotope enrichment in water by membrane distillation were studied in a 4-stage cascade. Two configurations of membrane distillation (MD) employing PTFE fat-sheet membranes were investigated, including direct contact MD and air gap MD. The first, direct contact MD is more efficient. It is characterized by high distillate flow rate. The temperature polarization coefficients were higher for direct contact MD. H/D and O-16/O-18 separation factors were determined in the 4-stage cascade.