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The circulating DNA found in human plasma is enriched for genomic DNA from minority tissues such as tumors, fetuses, and transplanted tissue. This sub fraction of blood has become an area of interest for development and disease as the nucleic acid recovered may represent a source of biomarkers for study. One milliliter of plasma typically yields between 1 ng and 50 ng of DNA. The current commercial DNA purification methods limit researchers' ability to scale their samples in both volume and number. Automated solutions are not available to process large numbers of samples with volumes greater than 1 ml, and manual methods can process up to 5 ml of plasma. Here we present a fully automated solution to extract DNA from 1-64 samples up to 8 ml in volume. The system provides an intuitive user interface to select run options and enter barcodes for reagents and samples. Any combination of sample volumes may be processed together in a single run. Samples are eluted in 50 µl of nuclease-free water in either plates or tubes. We have found that the performance of our system meets or exceeds common commercial alternatives over their common sample input volume. Citation Format: Sydnor T. Withers, Mary Dressler, Cristopher A. Cowan. Automated circulating DNA purification from large volumes of plasma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1516. doi:10.1158/1538-7445.AM2014-1516