Internally, heat-integrated distillation columns (HIDiC) and vapor recompression (VRC) constitute alternative design options to provide sustainable distillation processes. However, the design is often based on heuristic rules or the experience of the designer, as no systematic methodology driven by economics has been established so far. The increased complexity of heat-integrated columns can hardly be dealt with using simulation studies but rather calls for a systematic design procedure. A new design methodology is presented here; it builds on a superstructure, mixed-integer minimization of total annualized cost of operation and rigorous thermodynamic modeling. Optimal VRC and HIDiC designs are identified for the separation of binary, multicomponent, and nonideal mixtures and benchmarked against conventional distillation column designs. A small number of intermediate heat exchangers is optimal for these HIDiC configurations, eventually reducing to a single heat exchanger similar to VRC. Therefore, VRC designs are often more cost efficient due to simpler equipment. (C) 2012 American Institute of Chemical Engineers AIChE J, 2012