Individuals with chronic lymphocytic leukemia (CLL) face increased risk of severe COVID-19. This study from Sweden, a country with few mandatory restrictions at the onset of the pandemic, used 10 nationwide registers to compare risks of severe COVID-19 outcomes of PCR-verified SARS-CoV-2 infections through February 2023 in individuals with vs without CLL. From a population of 8,275,839 (6,653 CLL) individuals born 1930-2003, 2,088,163 first infections (1,289 CLL) were included. The 90-day all-cause mortality rate and adjusted relative risk (aRR [95% CI]) for individuals with CLL vs the general population was 24.8% (1.95 [1.58-2.41)) during Wild-type, 17.2% (2.38 [1.58-3.57)) during Alpha, 4.1% (0.71 [0.24-2.08]) during Delta, and 12.6% (1.49 [1.24-1.78]) during Omicron. Their mortality during Omicron was 0.6% (<
65 years), 5.4% (65-74 years), and 19.7% (>
75 years). Small molecule inhibitors (1.56 [1.03-2.37]) and corticosteroid usage (1.45 [1.04-2.02]) was associated with increased mortality. Next, we analyzed the all-cause mortality in the capital (Stockholm), widely affected by SARS-CoV-2 at the onset of the pandemic. Mortality in individuals with CLL increased by 55% during the first 6 months of 2020 vs 2019 and age- and sex aRR by June 30 was 1.53 [1.09-2.15] for individuals with CLL (P=.02) and 1.29 [1.25-1.33] for the general population (P<
.001). Collectively, a significantly increased risk of severe COVID-19 and death was observed among individuals with CLL in Sweden, particularly at the onset of the pandemic when few national protective measures were introduced, but also after Omicron emerged, emphasizing the need for a more pro-active pandemic strategy for CLL.