The detection of EGFR sensitizing and resistance mutations in advanced non-small cell lung cancer (NSCLC) patients is important for the selection and monitoring of EGFR tyrosine-kinase inhibitor (TKI) therapy. Droplet digital PCR (ddPCR) multiplex assays allow for sensitive and simultaneous detection of multiple mutations in cell-free DNA (cfDNA) with a minimum of extract needed and at lower cost. Patients were screened for EGFR TKI sensitizing mutations Ex19Del, L858R, L861Q, G719S and S768I, using a novel ddPCR pentaplex assay. Patients tested positive were subsequently monitored during treatment for the EGFR sensitizing mutation and two EGFR resistance mutations, T790M and C797S, using a ddPCR monitor triplex assay. The ddPCR multiplex assays enabled reliable detection of each mutation with a fractional abundance (FA) of at least 0.1%. For six patients, longitudinal data were analyzed and it was found that the ddPCR results reflected well the course of the disease and radiologic response. This study confirms that ddPCR on cfDNA supports the diagnosis and therapy selection, and shows that ddPCR multiplex assays on cfDNA could be a valuable additional diagnostic tool for therapy monitoring of NSCLC patients.