Strut-and-Tie modelling (STM) has been widely applied to design D-regions of reinforced concrete structures. For economic and environmental reasons there is a need for optimized Strut-and-Tie models. How to optimize Strut-and-Tie models considering multiple load combinations has not been investigated extensively in the literature. In order to address this gap in this paper, we propose a method to generate multi-load optimization-based Strut-and-Tie (MOST) models to design D-regions under multiple load combinations. The proposed generation method involves the determination of basis vectors for the load combinations and generation of the corresponding optimization-based Strut-and-Tie models for each of the basis vectors by topology optimization and truss extraction. The generated model is then used to design D-regions under multiple load combinations. In order to check the effectiveness of the proposed method, three alternative approaches for multiple load combinations are investigated and discussed. These approaches comprise: (1) using manually created Strut-and-Tie models, (2) adopting multi-load topology optimization resulting in a single Strut-and-Tie model, (3) generating individual Strut-and-Tie models for each of the considered load combinations. In this paper, three 2D and one 3D D-regions are investigated to compare the effectiveness and applicability of the different methods. It is found that the proposed method results in more economical designs than the three alternative approaches.@en