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Soluble epidermal growth factor receptor (sEGFR), a cell surface and serum protein derived from an alternately spliced human EGFR transcript, is recognized by 2 therapeutic antibodies approved by the US Food and Drug Administration: cetuximab and panitumumab. Therefore, circulating sEGFR is an unanticipated first target for both of these therapeutic antibodies, adding a new level of complexity to the understanding of EGF receptor biology that should be considered in the design of future clinical studies.