Abstract Background We examined differences in mortality among coronavirus disease 2019 (COVID-19) cases in the first, second, and third waves of the COVID-19 pandemic. Methods A retrospective cohort study of COVID-19 cases in Fulton County, Georgia, USA, reported to a public health surveillance from March 2020 through February 2021. We estimated case-fatality rates (CFR) by wave and used Cox proportional hazards random-effects models in each wave, with random effects at individual and long-term-care-facility level, to determine risk factors associated with rates of mortality. Results Of 75 289 confirmed cases, 4490 (6%) were diagnosed in wave 1 (CFR 31 deaths/100 000 person days [pd]), 24 293 (32%) in wave 2 (CFR 7 deaths/100 000 pd), and 46 506 (62%) in wave 3 (CFR 9 deaths/100 000 pd). Compared with females, males were more likely to die in each wave: wave 1 (adjusted hazard ratio [aHR], 1.5; 95% confidence interval [CI], 1.2–1.8), wave 2 (aHR 1.5, 95% CI, 1.2–1.8), and wave 3 (aHR 1.7, 95% CI, 1.5–2.0). Compared with non-Hispanic whites, non-Hispanic blacks were more likely to die in each wave: wave 1 (aHR, 1.4; 95% CI, 1.1–1.8), wave 2 (aHR, 1.5; 95% CI, 1.2–1.9), and wave 3 (aHR, 1.7; 95% CI, 1.4–2.0). Cases with any disability, chronic renal disease, and cardiovascular disease were more likely to die in each wave compared with those without these comorbidities. Conclusions Our study found gender and racial/ethnic disparities in COVID-19 mortality and certain comorbidities associated with COVID-19 mortality. These factors have persisted throughout the COVID-19 pandemic waves, despite improvements in diagnosis and treatment.