Background: Tumor mutation burden (TMB) is a biomarker of response to immune checkpoint blockade. The impact of TMB on outcomes with targeted therapies has not been explored. We hypothesized that TMB would inversely correlate with efficacy of targeted therapy in patients with EGFR mutant lung cancers proposing that additional mutations represent potential pathways for resistance with targeted therapies. Methods: We studied patients (pts) with metastatic EGFR mutant lung cancers with sensitizing exon 19 deletion (ex19del) or L858R variants treated with first/second generation tyrosine kinase inhibitors (TKIs) with pre-treatment targeted next generation sequencing (NGS; IMPACT) identified between January 2010 and September 2017. TMB was assessed in pre-TKI tissue defined as total non-synonymous mutations/Mb as assessed by the IMPACT platform. The effect of TMB on time on treatment (ToT) and overall survival (OS) were evaluated in univariate and multivariate analyses. Results: We identified 153 pts with metastatic EGFR mutant lung cancers profiled with MSK-IMPACT. Median TMB was 3.8 mutations/Mb (7.4 mutations/Mb for unselected lung cancers), but exhibited a wide range (0.82-17.9). In those with ≤ median TMB, ToT and OS were higher compared to those with > median TMB (ToT 17 vs. 10 months, HR 0.56, p = 0.006; OS 41 vs. 29 months, HR 0.52, p = 0.03). Within subgroups (never smokers, former smokers, TP53 co-mutant, age ≥ or < 65, man and woman), efficacy was consistently higher in those with ≤ median TMB. In multivariate analysis incorporating TMB, TP53 status, and EGFR ex19del vs. L858R, ToT remained improved in those with TMB ≤ median (HR 0.93, p = 0.02) but OS was not significant (HR 0.94, p = 0.3). Conclusions: Low TMB is associated with longer time on treatment in patients with metastatic EGFR mutant lung cancers treated with targeted therapy. This relationship is the reverse of that is seen with immune checkpoint blockade. TMB can serve as a relevant biomarker in lung cancers, with varied implications based on the nature of therapy being used.