Expression systems capable of growing to high cell densities are now readily available and are popular due to the benefits of increased product concentration. However, such high solids density cultures pose a major challenge for bioprocess engineers as choosing the right separation equipment and operating it at optimal conditions is crucial for efficient recovery. This study proposes a methodology for the rapid determination of suitable operating conditions for the centrifugal recovery of high cell density fermentation broths. An ultra scale-down (USD) approach for the prediction of clarification and dewatering levels achieved in a range of typical high-speed centrifuges is presented. Together with a visualisation tool, a Window of Operation, this provides for the rapid analysis of separation performance and evaluation of the available operating conditions, as an aid in the selection of the centrifuge equipment most appropriate for a given process duty. A case study examining centrifuge selection for the processing of a high cell density Pichia pastoris culture demonstrates the method. The study examines semi-continuous disc-stack centrifuges and batch-operated machines such as multi-chamber bowls and Carr Powerfuges™. Performance is assessed based on the variables of clarification, dewatering and product yield. Inclusion of limits imposed by the centrifuge type and design, and operation itself, serve to constrain the process and to define the Windows of Operation. The insight gained from the case study provides a useful indication of the utility of the methodology presented and illustrates the challenges of centrifuge selection for the demanding case of high solids concentration feed streams. © 2006 Wiley Periodicals, Inc.