Organic Rankine Cycle (ORC) systems have been recently considered for the promising application to Waste Heat Recovery (WHR) in automotive application. However, the design of ORC systems for highly transient operations typical of heavy-duty vehicles faces several challenges. This work extends the method of Design Space Exploration (DSE) to optimize the design of an ORC system for heavy-duty vehicle applications. The goal is to match the size of ORC system with the feature areas of driving cycle. Starting from drive cycle data, the feature areas are identified to represent the driving cycle. Then, a Weighted Least Square method is adopted to determine the initial design condition from feature areas, and based on the design condition, the initial ORC model is built for the further optimization. Particle Swarm Optimization (PSO) with parallel computation is adopted to optimize the performance of nonlinear ORC system with coupled constraints. The result shows that the optimal system can output 6.87% more power than the initial system and 20.08% more power than the inferior system over the feature areas of WHTC test. The analysis shown in this work also includes general design guidelines for optimizing the system architecture and optimally sizing the heat exchangers to improve the ORC thermal efficiency. (C) 2019 Elsevier Ltd. All rights reserved.