Background: Management of melanoma suffers from a lack of robust biomarkers of disease activity. In this study, we tested the ability of droplet digital PCR (ddPCR) to quantitatively measure levels of circulating BRAF and NRAS mutant DNA in the plasma of metastatic melanoma patients undergoing treatment with BRAF-targeted therapy or immunotherapy. Methods: We analyzed plasma samples from 45 patients with stage IV melanoma prospectively enrolled in the NYU Melanoma Biorepository program. All patients were commercially genotyped for BRAF V600E. SNaPshot assays were used to identify NRAS Q61 mutations in BRAF-WT tumors. Each patient had at least 3 serially collected plasma samples including one drawn prior to treatment, one or more after treatment began and one upon signs of disease progression. ddPCR was used to measure mutant copies/ml of BRAF V600E and NRAS Q61K/L/R DNA in plasma samples. Results: Among 45 patients, 28 patients had BRAF and 8 patients had NRAS tumor mutations. We extracted DNA from 151 plasma samples. Our preliminary results include analysis of 50 plasma samples from 10 BRAF-mutant and 5 NRAS-mutant patients. All BRAF V600E patients received BRAF inhibitor therapy and had partial responses followed by disease progression. Levels of circulating V600E DNA decreased with clinical response and/or increased with disease progression in 8/10 patients. In 3 patients with progressing disease, plasma samples drawn in-between imaging visits showed increasing BRAF mutant copies/ml up to 2 months prior to clinical scans. Among NRAS mutant patients, all were treated with Ipilimumab: 3 patients progressed, 1 had a near complete response, and 1 progressed and was then treated with Nivolumab. Levels of circulating Q61 DNA rose with disease progression and/or fell with clinical response in 5/5 immunotherapy treated patients. Conclusions: Our results indicate that ddPCR is able to measure clinically meaningful changes in the levels of BRAF and NRAS mutant copies/ml in the plasma of stage IV melanoma patients. This analytical platform has the potential for monitoring disease progression and patient response to both targeted and immune-based therapies, and may be a useful adjunct to imaging studies.