Background: This study examined lung cancer tumor samples from 163 Hispanic patients. Tumor-derived DNA was subjected to targeted-exome sequencing and ancestry analysis. Results: Among adenocarcinomas (n=120) in the Hispanic cohort, 31% had EGFR mutations, compared to 17% in a non-Hispanic White (NHW) control group (p < 0.001). A rare exon 19 mutation, W731R, was identified that conferred resistance to both erlotinib and AZD9291. KRAS (20% vs. 38%; p=0.002) and STK11 (8% vs. 16%; p=0.065) mutations occurred at lower frequency, and mutations in TP53 occurred at similar frequency (46% vs. 40%; p=0.355) in Hispanic and NHW patients, respectively. Within Hispanics, Indigenous American ancestry associated with a low rate of TP53 mutations (p=0.009) and may also associate with an elevated rate of EGFR mutations. Conclusions: We conclude that mutations in Hispanic lung adenocarcinoma patients differ in frequency from those in NHWs associated with their Indigenous American ancestry.