In this study, we introduce a new approach for predicting and analyzing the input multiplicity in reactive flash separation processes. Specifically, we have identified necessary conditions to detect these multiple states in reactive flash separations using reaction-invariant composition variables. The presence of the input multiplicity is studied for the reactive systems of MTBE and TAME production to illustrate the capabilities of our methodology. For these reactive systems, we report the existence of multiple states for different operating conditions. In summary, our strategy can be applied with any reactive system and thermodynamic model, assuming that all reactions are reversible and in thermodynamic equilibrium and the operating conditions are away from the retrograde region. In general, our method is a robust procedure for the multiplicity analysis in flash separation of multi-reactive and multi-component systems. (C) 2012 The Institution of Chemical Engineers. Published by Elsevier B.V. All rights reserved.