Background: This study evaluated the relationship between patients’ clinical and genomic characteristics and high tumor mutational burden (TMB) in the context of small cell lung cancer (SCLC). Methods: This was a retrospective cohort study using the deidentified Flatiron Health-Foundation Medicine Clinico-Genomic Database linking clinical electronic health records and comprehensive genomic profiling (CGP) data from January 2011-September 2018. Patients ≥18 years with confirmed SCLC pathology, FoundationOne® genomic profiling data, and chemotherapy treatment were included. We examined treatment patterns, genomic alterations, TMB score, survival and the association of clinical and genomic variables with high TMB as determined a by multivariate logistic regression. High TMB (TMB-H) was defined as ≥10 mutations/megabase (mut/Mb). Results: A total of 186 patients were included in the study. CGP test results were reported prior to initiation of first-line (1L) treatment in 6.9% of patients and prior to second-line (2L) treatment in 65.6% of patients. 1L and 2L treatment patterns were similar for patients with high and low TMB scores. The most frequent 1L therapy was a combination of carboplatin and etoposide (65.3% in TMB-H patients, 67.3% in non TMB-H patients). A total of 95 patients continued to 2L therapy, and topotecan monotherapy was the most frequent 2L therapy (12.0% in TMB-H patients, 15.4% in non TMB-H patients). The median duration of 1L and 2L treatment in TMB-H and non TMB-H patients were 11.1 vs. 7.9 months for 1L and 7.9 vs. 5.6 months for 2L (adjusted P values of 0.76 and 0.28 respectively). The most frequent short variant mutations (including variants of unknown significance) observed were in TP53(90.86%), RB1(65.05%), LRP1B(32.79%), and FAT3(20.96%). Loss of heterozygosity in TP53 was confirmed in 62.4% of patients and high microsatellite instability was recorded in 0.7% of patients tested. TMB score was determined for 179 patients. The mean (SD) TMB score was 9.75 (7.89), the median (IQR) TMB score was 8.70 (5.2-13.0), and 41.9% had a TMB score ≥10. Variables significantly associated with a high TMB score at P≤ 0.05 were short variants of LRPB1, FAT3, MLL3, MED12, and NOTCH3. The median overall survival from time of diagnosis was 14.9 months in patients with high TMB and 14.7 months in those with low TMB, with an adjusted hazard ratio 0.985 (95% CI 0.648, 1.498). Conclusions: Treatment patterns and survival did not differ by TMB status.