The separation of mixtures containing more than two components in significant amounts. If all of the components are present in small amounts except for two, the mixture can be treated as a binary and the same design principles apply as for binary. Complexity arises from the number of components present. For a given pressure and a particular component composition in the liquid phase, there no longer exists a unique vapour composition and temperature. These depend on the amount and type of the other components present. For hydrocarbons, K-factors can be used. It is also possible to use vapour pressure data for ideal systems. Calculation methods often depend essentially on an assumed temperature profile that can be used to link vapour and liquid phase compositions for a given column pressure. Checks are made to ensure that the sum of the mole fractions in the liquid and vapour phases are equal unity. The process is repeated until the differences in compositions or flows at product take-off or at the feed point are below an acceptable figure. This assumes equimolar flows in any section. (p. 247) Together with knowledge of feed condition and reflux ratio, the flow in the column profile can be calculated. Short-cut methods are available for preliminary investigations. The usual ones are the methods of Fenske, Underwood, Erbar–Maddox, and Smith–Brinkley. Two of the earliest rigorous methods were developed by Lewis–Matheson and Thiele–Geddes.

To perform multicomponent distillation calculations requires the introduction of the concept of key components. These are the components between which the split between components is required and must be present in appreciable amounts in the feed, and effectively all of one will appear in the distillate (light key) and all of the other in the bottoms (heavy key). More correctly, the light key is the lightest component in the bottoms whose composition is to be specified. Some simplified calculations assume that all LLK (lighter than light key) components are absent from the bottoms and all HHK (heavier than heavy key) from the distillate. The key components effectively unlock the problem.