Centralized air distribution systems in non-residential buildings are characterized by an extensive air distribution network, that has to be built in a building environment with finite degrees of freedom. The ductwork layout, i.e., the network structure of the ducts, as well as the number and location of the fans, has a large impact on the total cost and performance of the air distribution system. Nevertheless, existing air distribution system design methods are limited to the sizing of each duct (and fan) in the network. The layout itself is considered predetermined, and thus not explicitly taken into account for optimization. In this paper, we meet this shortcoming by presenting the air distribution network design optimization method, that is able to calculate the optimal air distribution system configuration, i.e., the optimal layout and duct and fan sizes, while minimizing the total cost of the air distribution system. A multi-start local search algorithm is developed, consisting of a constructive and a local search phase. In the first phase, multiple air distribution system configurations are generated, and evaluated for feasibility. In the local search phase, all feasible solutions are further optimized in terms of material costs by decreasing and increasing the duct diameters following the steepest descent/mildest ascent approach. An application of the algorithm on a realistic test case demonstrates its usefulness in practice. (C) 2018 Elsevier B.V. All rights reserved.