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When it comes to monitoring of huge structures, main issues are limited time, high costs and how to deal with the big amount of data. In order to reduce and manage them, respectively, methods from the field of optimal design of experiments are useful and supportive. Having optimal experimental designs at hand before conducting any measurements is leading to a highly informative measurement concept, where the sensor positions are optimized according to minimal errors in the structures’ models. For the reduction of computational time a combined approach using Fisher Information Matrix and mean-squared error in a two-step procedure is proposed under the consideration of different error types. The error descriptions contain random/aleatoric and systematic/epistemic portions. Applying this combined approach on a finite element model using artificial acceleration time measurement data with artificially added errors leads to the optimized sensor positions. These findings are compared to results from laboratory experiments on the modeled structure, which is a tower-like structure represented by a hollow pipe as the cantilever beam. Conclusively, the combined approach is leading to a sound experimental design that leads to a good estimate of the structure’s behavior and model parameters without the need of preliminary measurements for model updating.