Background: Lung cancer is by far the leading cause of cancer death worldwide, with non-small cell lung cancer (NSCLC) accounting for the majority of cases. Genotype-directed therapy becomes a promising method for cancer treatment beside surgery and chemo-radiotherapy. Liquid biopsy using massive parallel sequencing has emerged as a non-invasive alternative procedure in profiling cancer driver mutations. In this study, we report the spectrum of clinically actionable mutations in plasma circulating tumor DNA of 299 non-small cell lung cancer patients using ultra-deep massive parallel sequencing with unique identifier tagging. Methods: Plasma circulating tumor DNA was extracted, ligated with unique identifier (Swift Bioscience), enriched of the target coding regions of EGFR, KRAS, NRAS, BRAF and the breakpoints of ALK, ROS1 (IDT) and sequenced using NextSeq 550 (Illumina) at mean coverage depth of 20,000X. Results: Out of 299 patients tested, 128 (42,8%) carried driver mutations. Genetic alterations were identified in EGFR (79 samples, 26,4%), KRAS (30 samples, 10%), ALK (7 samples, 2,34%), ROS1 (6 samples, 2%), BRAF (3 samples, 1%). There was no sample with NRAS mutation. In 79 EGFR-cases, there were 23 carry two pathogenic variants. 28 mutation types of EGFR were found including 19 indels and 9 missense variants L858R and T790M were the major ones. One case was found with concomitant EGFR and BRAF. Our study showed the spectrum and frequency of the cancer driver mutations detected in liquid biopsy was correlated to those detected in tissue biopsy samples. Conclusions: For the first time the spectrum of mutation types in liquid biopsy of Vietnamese NSCLC patients were investigated and showed the correlation with those detected in tissue biopsy samples.