Background: Small cell lung cancer (SCLC) is a neuroendocrine tumor characterized by early distant metastasis. NOTCH signaling controls neuroendocrine cell differentiation. In mouse models, NOTCH pathway suppression was associated with lower liver metastasis, but there is no clinical data supporting this observation in SCLC patients. Here we examined NOTCH (1,2 and 3) mutation in different SCLC tumor biopsy sites and, more importantly, correlated NOTCH mutation with patient survival Methods: A cohort of 67 extensive stage SCLC patients (2012 to 2017) with clinical and targeted exome-sequencing data on their tumors was used. The median follow-up was 9.4 (range: 0.5 – 78.6) months. We analyzed NOTCH mutations based upon the site of tumor biopsy using Chi-square. The association of NOTCH 1,2, or 3 mutations with progression-free survival (PFS) and overall survival (OS) was examined using Kaplan–Meier method. The predictive values of NOTCH 1,2, or 3 mutations on PFS and OS were estimated using multivariable Cox proportional hazards regression model adjusting known clinical and other genomic prognostic features. Results: Among 161 genes targeted by the exome sequencing panel with a mutation frequency of > 3, NOTCH family mutations were the most which significantly found in lung compared to other biopsy sites (73%, N= 19, p = 0.008). A total of 19 patients were identified with either NOTCH1, 2 or 3 mutations. The majority of mutations were categorized as missense (82%, total N = 19/23). NOTCH 1 was the most commonly mutated family member (N = 12), followed by NOTCH 2 (N = 6) and NOTCH 3 (N = 5). Most notably, out of 23 total NOTCH mutations, only one mutation, in NOTCH 2, (p = 0.026) was observed in liver specimens. After adjusting for the effects of confounders such as MYC mutation (important tumor suppressor and downstream gene in NOTCH pathway), sex, age, stage, NOTCH mutation (1, 2, and 3 combined) was significantly associated with increased OS (p = 0.032, HR:0.37) and PFS (p = 0.018, HR = 0.033). Conclusions:NOTCH mutation in SCLC is more frequent in lung compared to metastatic biopsy sites, including liver, and is associated with significantly improved survival.