Background: NF1 is a tumor suppressor that negatively regulates Ras, thus NF1 mutant tumors may also be sensitive to inhibitors of MAP kinase signaling. NF1 variants occur in lung cancer, but their clinical significance is unknown. We evaluated clinical and molecular characteristics of NF1 mutant lung cancers, with comparison to KRAS mutant tumors. Methods: From 07/13-10/14, 591 lung tumors at our institution underwent targeted next generation sequencing (NGS) for mutations and copy number alterations in a 275 gene panel. NF1 and KRAS cohorts were identified, with clinical and genomic analysis. Fisher’s exact test was used to compare frequency of gene mutations between cohorts. Results: Among 591 pts, 60 had NF1 mutations (10%) and 143 (24%) had KRAS mutations (Stage IV: NF1 26, 43%; KRAS 58, 41%). 15 NF1 mutations (25%) occurred with other driver mutations (BRAF (2); ERBB2 (2); KRAS (9); XRAS (2)). There were 73 unique NF1 variants: single copy deletion (1), splice site (12), loss of function/predicted damaging (49), predicted benign (11). 10 tumors had > 1 mutation. Tumor pathology was diverse: adenocarcinoma (38, 63%); squamous cell carcinoma (11, 18%); large cell neuroendocrine (2, 3%); mixed small cell carcinoma (2, 3%); other (7, 11%). In contrast, KRAS mutations (G12C:51, G12D:22, G12V:27, Q61H:8, other:35) occurred in adenocarcinomas (138, 97%) and seldom with other driver mutations (2, 1%). Both mutations were common in former ( > 10 pack years) or current smokers (NF1 49, 82%; KRAS 120, 84%). Among pts without co-mutation, TP53 mutations/2-copy deletions occurred more often with NF1 mutation (33, 65%) than KRAS mutation (47, 35%) (p < .001). Similarly, LKB1 mutations occurred in 8 (16%) NF1 mutant tumors and 33 (25%) KRASmutant tumors (p = .24). Conclusions: NF1 mutations define a unique population of 10% of non-small cell lung carcinoma (NSCLC). NF1 and KRAS mutations present in similar pt populations. NF1 mutations occur more often with other driver mutations and with coexisting TP53 mutations than KRAS mutations. Therapeutic strategies targeting KRAS activation, such as MEK inhibitors, may warrant investigation in NF1 mutant tumors. Tumor suppressor inactivation patterns in these tumors may help further define novel treatment strategies.