The reliable detection of circulating tumor DNA is a particular technical challenge due to the low frequency of circulating tumor DNA in the blood of cancer patients. At present time, a variety of techniques is applied, with no apparent gold standard. To meet the conditions of high analytical sensitivity and specificity, we developed a novel amplification refractory mutation system (ARMS) qPCR protocol. Three ARMS assays to detect BRAF V600E, PTEN T167A and NRAS Q61L mutations were designed for qPCR. Assay performance was tested in spike-in experiments. Tumor DNA derived from cell culture cells was serially diluted (down to one tumor copy) into a large constant background of wild-type DNA from PBMCs. The detection limit of ARMS qPCR was increased by using a polymerase (SNPase) specifically designed for point mutation detection. We termed this approach “SNPase-ARMS qPCR”. High sensitivity and precision of the SNPase-ARMS qPCR could be demonstrated with the BRAF V600E and PTEN T167A assays. Here, one tumor copy could reliably be detected among 200 000 wild-type DNA molecules. The NRAS Q61L assay reached a sensitivity of three tumor copies in a background of 200 000 wild-type DNA. To show the clinical applicability of the method, the BRAF V600E assay was also applied on a small cohort of melanoma patients. Melanoma patients with advanced disease yielded higher plasma levels of BRAF V600E, while patients with lower stages of melanoma were negative.