ImportanceWith the ongoing relaxation of guidelines to prevent COVID-19 transmission, particularly in hospital settings, medically vulnerable groups, such as patients with cancer, may experience a disparate burden of COVID-19 mortality compared with the general population.ObjectiveTo evaluate COVID-19 mortality among US patients with cancer compared with the general US population during different waves of the pandemic.Design, Setting, and ParticipantsThis cross-sectional study used data from the Center for Disease Control and Prevention’s Wide-Ranging Online Data for Epidemiologic Research database to examine COVID-19 mortality among US patients with cancer and the general population from March 1, 2020, to May 31, 2022. The number of deaths due to COVID-19 during the 2021 to 2022 winter Omicron surge was compared with deaths during the preceding year’s COVID-19 winter surge (when the wild-type SARS-CoV-2 variant was predominant) using mortality ratios. Data were analyzed from July 21 through August 31, 2022.ExposuresPandemic wave during which the wild-type variant (December 2020 to February 2021), Delta variant (July 2021 to November 2021), or Omicron variant (December 2021 to February 2022) was predominant.Main Outcomes and MeasuresNumber of COVID-19 deaths per month.ResultsThe sample included 34 350 patients with cancer (14 498 females [42.2%] and 19 852 males [57.8%]) and 628 156 members of the general public (276 878 females [44.1%] and 351 278 males [55.9%]) who died from COVID-19 when the wild-type (December 2020-February 2021), Delta (July 2021-November 2021), and winter Omicron (December 2021-February 2022) variants were predominant. Among patients with cancer, the greatest number of COVID-19 deaths per month occurred during the winter Omicron period (n = 5958): at the peak of the winter Omicron period, there were 18% more deaths compared with the peak of the wild-type period. In contrast, among the general public, the greatest number of COVID-19 deaths per month occurred during the wild-type period (n = 105 327), and at the peak of the winter Omicron period, there were 21% fewer COVID-19 deaths compared with the peak of the wild-type period. In subgroup analyses by cancer site, COVID-19 mortality increased the most, by 38%, among patients with lymphoma during the winter Omicron period vs the wild-type period.Conclusions and RelevanceFindings of this cross-sectional study suggest that patients with cancer had a disparate burden of COVID-19 mortality during the winter Omicron wave compared with the general US population. With the emergence of new, immune-evasive SARS-CoV-2 variants, many of which are anticipated to be resistant to monoclonal antibody treatments, strategies to prevent COVID-19 transmission should remain a high priority.