Background/Objectives: The cobas EGFR test v2, used for detecting EGFR mutations, can yield invalid results due to internal control (IC) issues, such as "IC not detected", "IC out of range: high Ct value", or "IC out of range: low Ct value". This study aimed to examine the incidence of invalid cobas results and explored the mechanism behind low IC Ct values. Methods: We retrospectively reviewed invalid cases, linking undetectable or high IC Ct values to inadequate DNA from small biopsies, as determined by conducting a pathological review. Cases with low IC Ct values were further tested, with the hypothesis of EGFR amplification confirmed using Sanger sequencing, the Idylla assay, next-generation sequencing (NGS), and fluorescence in situ hybridization (FISH). Results: Among 4148 cases, the incidence of invalid results was 0.99% (41/4148). In four cases with low IC Ct values, EGFR amplification was confirmed using alternative methods with successful cobas testing on diluted DNA. Conclusions: These findings suggest that EGFR amplification, rather than specimen inadequacy, is the cause of low IC Ct results, making rebiopsy unnecessary. Alternative assays or diluted DNA allow for successful EGFR testing.