Introduction: Previously, we reported the frequency of epidermal growth factor receptor (EGFR) and KRAS mutations in nonsmall-cell lung cancer (NSCLC) patients in Latin America. The EGFR mutation frequency was found between Asian (40%) and Caucasian (15%) populations. Here, we report the updated distribution of NSCLC mutations. Methods: A total of 5738 samples from NSCLC patients from Argentina (1713), Mexico (1417), Colombia (1939), Peru (393), Panama (174), and Costa Rica (102) were genotyped for EGFR and KRAS. Results: The median patient age was 62.2 ± 12.3 years; 53.5% were women, 46.7% had a history of smoking, and 95.2% had adenocarcinoma histology. The frequency of EGFR mutations was 26.0% (95% confidence interval [CI], 24.9-27.1; Argentina, 14.4% [12.8-15.6]; México, 34.3% [31.9-36.7]; Colombia, 24.7% [22.8-26.6]; Peru, 51.1% [46.2-55.9]; Panamá, 27.3 [20.7-33.9]; and Costa Rica, 31.4% [22.4-40.4]). The frequency of KRAS mutations was 14.0% (9.1-18.9). In patients with adenocarcinoma, EGFR mutations were independently associated with gender (30.7% females vs. 18.4% males; p < 0.001), nonsmoker status (27.4% vs. 17.1%, p < 0.001), ethnicity (mestizo/indigenous, 35.3% vs. Caucasian, 13.7%, p < 0.001), and the absence of KRAS mutation (38.1% vs. 4.7%; p < 0.001). The overall response rate to EGFR tyrosine kinase inhibitors was 60.6% (95% CI, 52-69), with a median progression-free survival and overall survival of 15.9 (95% CI, 12.420.6) and 32 months (95% CI, 26.5-37.6), respectively. Conclusion: Our findings support the genetic heterogeneity of NSCLC in Latin America, confirming that the frequency of EGFR mutations is intermediate between that observed in the Asian and Caucasian populations.