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Abstract Key Points Question: What are the risks of severe outcomes from COVID-19 in people with immunocompromising/immunosuppressive (IC/IS) conditions in the Omicron era? Findings: This systematic review and meta-analysis found increased risk of severe outcomes for people with IC/IS conditions (e.g., autoimmunity, cancer, liver disease, renal disease, transplant) compared with people without the respective conditions. Of all meta-analyzed conditions, transplant recipients had the highest risk of severe COVID-19 outcomes, compared with non-transplant recipients or the general population. Meaning: People with IC/IS conditions remain at increased risk of severe outcomes from COVID-19 during the Omicron era; continued preventative measures and personalized care are crucial. Importance This is the first meta-analysis to investigate the risk of severe outcomes for individuals with immunocompromising/immunosuppressive (IC/IS) conditions specifically in the Omicron era. Objective To assess the risk of mortality and hospitalization from COVID-19 in people with IC/IS conditions compared with people without IC/IS conditions during the Omicron era. Data Sources A systematic search of Embase, MEDLINE, PubMed, Europe PMC, Latin American and Caribbean Health Sciences Literature, Cochrane COVID-19 Study Register, and WHO COVID-19 Database was performed to identify studies published between 1 January 2022 and 13 March 2024. Study Selection Inclusion criteria were observational studies that included people (all ages) with at least 1 of the following conditions: IC/IS unspecified groups, transplant (solid organ, stem cells, or bone marrow), any malignancy, autoimmune diseases, any liver diseases, chronic or end-stage kidney disease, and advanced/untreated HIV. In total, 72 studies were included in the review, of which 66 were included in the meta-analysis. Data Extraction and Synthesis Data were extracted by one reviewer and verified by a second. Studies were synthesized quantitively (meta-analysis) using random-effect models. PRISMA guidelines were followed. Main Outcomes and Measures Evaluated outcomes were risks of death, hospitalization, intensive care unit (ICU) admission, and any combination of these outcomes. Odds ratios, hazard ratios, and rate ratios were extracted; pooled relative risk (RR) and 95% confidence intervals (CI) were calculated. Results Minimum numbers of participants per IC/IS condition ranged from 12 634 to 3 287 816. Risks of all outcomes were increased in people with all meta-analyzed IC/IS conditions compared with people without the respective conditions. Of all meta-analyzed IC/IS conditions, transplant recipients had the highest risk of death (RR, 6.78; 95% CI, 4.41-10.43; P <.001), hospitalization (RR, 6.75; 95% CI, 3.41-13.37; P <.001), and combined outcomes (RR, 8.65; 95% CI, 4.01-18.65; P <.001), while participants in the unspecified IC/IS group had the highest risk of ICU admission (RR, 3.38; 95% CI, 2.37-4.83; P <.001) compared with participants without the respective IC/IS conditions or general population. Conclusions In the Omicron era, people with IC/IS conditions have a substantially higher risk of death and hospitalization from COVID-19 than people without these conditions.