Elevated circulating cell-free DNA (CFD) levels were found in patients with cancer. The standard CFD assays are work-intensive and expensive. The aim was to evaluate in patients with cancer a new simple CFD assay. In mice inoculated with cancer cells, CFD levels correlated with tumor size. Compared with healthy subjects, 38 patients with colorectal cancer (CRC) had higher preoperative CFD levels (798 ± 409 vs 308 ± 256 ng/mL; P < .0001). Compared with patients free of disease at 1 year, CFD levels were elevated in patients who remained with disease or died (DD). CFD correlated with DD (P = .033), and a combined index of carcinoembryonic antigen × CFD exhibited a better correlation to DD than did pathologic staging (P = .0027 vs P = .0065). For patients with CRC, CFD levels were prognostic of death and disease. A large prospective study will need to be performed to truly evaluate the efficacy of this method for early detection, follow-up, and evaluation of patient response to treatment.