Small cell lung cancer (SCLC) has the strongest association with smoking among lung cancers. The characteristics of never-smokers with SCLC is not known.Is the clinical characteristics, prognostic factors, survival, genomic alterations, and tumor mutational burdens of SCLC in patients who have never smoked different from those who have smoked?and Methods: A retrospective multicenter cohort study of patients with clinician-confirmed SCLC was performed using a longitudinal and nationally representative electronic medical records database. Smoking history was assessed through technology-enabled abstraction and confirmed for never-smokers via chart review. Genomic characteristics of never-smoker SCLC patients were examined using a next-generation sequencing-based gene panel and whole exome sequencing.100 of 5632 (1.8%) SCLC patients were never-smokers. Relative to smokers, never-smokers were more likely to be female (66.0% vs. 52.4%; p=0.009) and present with extensive-stage (70.0% vs. 62.2%; 0.028). Never-smokers had a higher proportion of patients in age-groups 35-49 years (7.0% vs. 3.0%; p=0.006) and ≥80 years (17.0% vs. 8.2%; p=0.006). Known risk factors for lung cancer were found in <20% of never-smokers. There were no overall survival differences among never-smokers and smokers. Among patients with available genomic data (N=9), never-smoker SCLC were characterized by lower tumor mutational burden, a lower frequency of TP53 mutations as well as absence of mutational signatures related to tobacco exposure.The sex and age-specific distribution of SCLC among never-smokers, along with differences identified by genomic analyses suggest a distinct biology of SCLC in never-smokers compared to smokers.