Plasma-based tumor mutational profiling is arising as a reliable approach to detect primary and therapy-induced resistance mutations required for accurate treatment decision making. Here, we compared the FDA-approved Cobas® EGFR Mutation Test v2 with the UltraSEEK™ Lung Panel on the MassARRAY® System on detection of EGFR mutations, accompanied with preanalytical sample assessment using the novel Liquid IQ® Panel. 137 cancer patient-derived cell-free plasma samples were analyzed with the Cobas® and UltraSEEK™ tests. Liquid IQ® analysis was initially validated (n = 84) and used to determine ccfDNA input for all samples. Subsequently, Liquid IQ® results were applied to harmonize ccfDNA input for the Cobas® and UltraSEEK™ tests for 63 NSCLC patients. The overall concordance between the Cobas® and UltraSEEK™ tests was 86%. The Cobas® test detected more EGFR exon19 deletions and L858R mutations, while the UltraSEEK™ test detected more T790M mutations. A 100% concordance in both the clinical (n = 137) and harmonized (n = 63) cohorts was observed when >10 ng of ccfDNA was used as determined by the Liquid IQ® Panel. The Cobas® and UltraSEEK™ tests showed similar sensitivity in EGFR mutation detection, particularly when ccfDNA input was sufficient. It is recommended to preanalytically determine the ccfDNA concentration accurately to ensure sufficient input for reliable interpretation and treatment decision making.