Structural optimization has become an important tool for structural designers. It helps them to find innovative design solutions and structural forms with a better exploitation of materials as well as decreased structures' self-weight and minimum material costs. In this article, the Calatrava Bridge over the Grand Canal of Venice is used as a prototype. Several tentative starting models are identified by considering bridge's abutment deformability through spring-damper elements and introducing prestressing stiffening cables along two bottom arches of the bridge. Afterwards members' thickness optimization is carried out and the results are compared in terms of weight reduction and horizontal force level. The results evidence that thought the use of structural optimization, more reasonable thickness distribution of steel members can be obtained, while reducing remarkably both the self-weight and the horizontal forces of this bridge against the abutment. © 2014 Taylor & Francis Group.