BACKGROUND Microfluidic-based systems are ideal for handling small microliter volumes of samples and reagents, but 'real-world' or clinical samples for bioanalysis are often on the milliliter scale. We aimed to develop and validate a large-volume centrifugal or compact disc-based device for blood plasma separation, capable of processing 2 ml undiluted blood samples. RESULTS This automated blood sample preparation device was shown to yield high purity plasma in less than half the time of commercial plasma preparation tubes, while enabling integration with downstream analysis and detection steps. CONCLUSIONS This article draws upon a novel large-volume device to further illustrate the challenges in combining microfluidics structures with large-volume samples and the implications for sample-driven microfluidics systems.