question: Background: The impact of COVID-19 has disproportionately affected every aspect of cancer care and research-from introducing new risks for patients to disrupting the delivery of treatment and continuity of research. Variation in risk of adverse clinical outcomes in COVID-19 patients by cancer type has been reported from relatively small cohorts. Gaps in understanding effects of COVID-19 on cancer patients can be addressed through the study of a well-constructed representative cohort. The NCATS' National COVID Cohort Collaborative (N3C) is a centralized data resource representing the largest multi-center cohort of COVID-19 cases and controls nationwide. We aimed to construct and characterize the cohort of cancer patients within N3C and identify risk factors for all-cause mortality from COVID-19. Methods: From the harmonized N3C clinical dataset, we used 3,295,963 patients from 39 medical US centers to construct a cancer patient cohort. We restricted analyses to adults ≥18 yo with a COVID-19 positive PCR or antigen test or ICD-10-CM diagnostic code for COVID-19 between 1/1/2020 and 2/14/2021. We followed N3C definitions where each lab-confirmed positive patient has one single index encounter. A modified WHO Clinical Progression Scale was used to determine clinical severity. All analyses were performed in the N3C Data Enclave on the Palantir platform. Results: A total of 372,883 adult patients with cancer were identified from the N3C cohort;54,642 (14.7%) were COVID-19 positive. Most common represented cancers were skin (11.5%), breast (10.2%), prostate (8%), and lung cancer (5.6%). Mean age of COVID-19 positive patients was 61.6 years (SD 16.7), 47.3% over 65yo, 53.7% females, 67.2% non-Hispanic White, 21.0% Black, and 7.7% Hispanic or Latino. A total of 14.6% were current or former smokers, 22.3% had a Charlson Comorbidity Index (CCI) score of 0, 4.6% score of 1 and 28.1% score of 2. Among hospitalized COVID-19 positive patients, average length of stay in the hospital was 6 days (SD 23.1 days), 7.0% patients had died while in their initial COVID-19 hospitalization, 4.5% required invasive ventilation, and 0.1% extracorporeal membrane oxygenation. Survival probability was 86.4% at 10 days and 63.6% at 30 days. Older age over 65yo (Hazard ratio (HR) = 6.1, 95%CI: 4.3, 8.7), male gender (HR = 1.2, 95%CI: 1.1, 1.2), a CCI score of 2 or more (HR = 1.15, 95%CI: 1.1, 1.2), and acute kidney injury during hospitalization (HR = 1.3, 95%CI: 1.2, 1.4) were associated with increased risk of all-cause mortality. Conclusions: Using the N3C cohort we assembled the largest nationally representative cohort on patients with cancer and COVID-19 to date. We identified demographic and clinical factors associated with increased all-cause mortality in cancer patients. Full characterization of the cohort will provide further insights on the effects of COVID-19 on cancer outcomes and the ability to continue specific cancer treatments.