Background: Comprehensive real-world evidence of the virulence of COVID-19 Omicron, Delta, and Alpha variants as well as the effectiveness of booster vaccinations in patients with cancer are lacking. We aimed to fill in these gaps for cancer patients and provide essential insights on the management of the fast-evolving pandemic by leveraging the nationally-representative electronic medical records from the National COVID Cohort Collaborative (N3C) registry. Methods: The virulence of COVID-19 variants was examined according to severe outcomes of infected patients with cancer, compared with non-cancer patients, using the N3C data between 12/01/2020 and 02/03/2022. Variants were inferred according to the time periods of variant dominance at > 95% accuracy. The Cox proportional hazards model was employed to evaluate the effects of COVID-19 variants, adjusting for age, gender, race/ethnicity, geographic regions, vaccination status, cancer types, smoking status, cancer treatments, and adjusted Charlson Comorbidity Index (CCI). Results: Our study cohort included 114,195 COVID-19 patients with cancer and 160,493 without cancer as control. Among them, 52,539 (21%) were infected by Omicron, 82,579 (33%) by Delta, and 115,200 (46%) by Alpha variants. Prior to the COVID-19 breakthrough infection, 7%, 22%, 3%, and 69% were vaccinated with 1 dose, 2 doses, a booster, or unvaccinated respectively. The proportions of hospitalization and death among patients with vs without cancer were 40% and 7% vs 18% and 0.4%, respectively. Characteristics of the cancer subcohort are summarized in the Table. Our analysis showed dramatically lower risks of severe outcomes for patients who were infected by Omicron (HR 0.42, 95%CI: 0.38 – 0.46) and slightly lower risks for Delta (HR 0.93, 95%CI: 0.89 – 0.98) compared with those infected by Alpha, after adjusting for other demographic clinical risk factors, and vaccination status. This trend remained similar in subgroups of patients with solid tumors, hematologic malignancies, or without cancer. Similar associations were observed when virulence was evaluated in association with mortality. The effectiveness of booster vaccinations varied across sub-cohorts stratified by variants and cancer types. Booster shots reduced the risk of severe outcomes for patients with solid tumors infected by Omicron variant or hematologic malignancies infected by Delta variants. Conclusions: Our work provides up-to-date and comprehensive real-world evidence of the virulence of COVID-19 variants in patients with cancer. Omicron variant showed significantly reduced virulence for different cancer types.