Biogas plants have to be continuously or periodically mixed to ensure the homogenization of fermenting and fresh substrate. Externally installed mixers provide easier access than submerged mixers but concerns of insufficient mixing deter many operators from using this technology. In this paper, a new approach to improve homogenization of the substrate mixture is proposed by optimizing external mixer configurations across a wide range of rheological properties. Robust optimization of a biogas reactor is coupled with CFD simulations to improve parameters for the angles of inflow and the position of the substrate outlet in a large-scale fermenter. The optimization objective is to minimize the area in the tank which is poorly mixed. We propose to define this ‘‘dead volume zone'' as the region in which the velocity magnitude during mixing falls below a certain threshold. Different dry substance contents are being investigated to account for the varying rheological properties of different substrate compositions. The velocity thresholds are calculated for each dry substance content from the mixer-tank configuration of a real biogas reactor in Brandenburg, Germany (BGA Warsow GmbH & Co. KG). The robust optimization results comprising the whole range of rheological properties are compared to simulations of the original configuration and to optimization results for each individual dry substance content. The robust CFD-based optimized configurations reduce the dead volume zones significantly across all dry substance contents compared to the original configuration. The outcomes of this paper can be particularly useful for plant manufacturers and operators for optimal mixer placement in industrial size biogas fermenters.