An optimal design strategy for membrane networks separating multicomponent gas mixtures based on an approximate permeator model and mixed-integer nonlinear programming (MINLP) is proposed. A permeator system superstructure is used to embed a very large number of possible network configurations and allows the permeator feed-side pressure to be fixed or a design variable. A MINLP design model is developed to minimize the total annual process cost by simultaneous optimization of the permeator configuration and operating conditions. Case studies for the separation of acid gases (CO2 and H2S) from crude natural gas mixtures with spiral-wound permeators are presented. Permeator configurations are derived for different number of separation stages for both continuous and discrete membrane areas. The method is sufficiently robust to handle product compositions that vary five orders of magnitude. The proposed approach provides an efficient methodology for preliminary screening of multi-stage membrane separation systems for multicomponent gas mixtures. (C) 2000 Elsevier Science Ltd. All rights reserved.