Background: Individuals with compromised immune systems are particularly vulnerable to COVID-19. Although several studies have assessed factors associated with COVID-19-related hospitalisation and mortality in the general population, few studies have focused specifically on immunocompromised populations. Methods: With the approval of NHS England, we conducted a cohort study using the OpenSAFELY platform covering successive waves of COVID-19 (wave 1, alpha, delta, omicron BA.1/BA.2, JN.1). In each wave, we included adults in five hierarchically assigned immunocompromised subgroups: solid organ transplant (SOT); bone marrow compromise (BMC); active radio- or chemo-therapy (RCT); active immunosuppressive medication (IMM); and primary or acquired immunodeficiency (IMD). In each subgroup, we estimated wave-specific rates of severe COVID-19-related outcomes and relative hazards according to vaccination status, sociodemography (age, ethnicity, deprivation), and comorbidities, as determined at the start of the wave. Findings: We included between 475,360 (BA.1/BA.2 wave) and 508,545 (JN.1 wave) immunocompromised individuals per wave. Across successive waves, individuals with SOT, BMC, or RCT exhibited higher rates of severe COVID-19 than those with IMM or IMD. Compared with being unvaccinated in the past 26 weeks, vaccination in the 12 weeks preceding the start of a wave was associated with a consistent reduction in severe COVID-19, albeit with a smaller effect size among SOT recipients relative to other subgroups. Though attenuated compared to earlier waves, this association persisted during JN.1 dominance (adjusted hazard ratios of 0.88 [95% CI 0.60–1.30] for SOT, 0.64 [95% CI 0.53–0.77] for BMC, 0.68 [95% CI 0.44–1.03] for RCT, 0.68 [95% CI 0.52–0.88] for IMM, and 0.68 [95% CI 0.55–0.82] for IMD). Older age and increased comorbidity count were strongly associated with increased risk of severe COVID-19 across subgroups and waves. Interpretation: The risk of COVID-19 varies substantially within and across immunocompromised subgroups. The presence of other comorbidities was strongly associated with the risk of severe COVID-19 across successive waves. Primary vaccination and successive booster doses were associated with a consistent reduction in severe COVID-19 in this high-risk population, including during the JN.1 wave. Funding: National Institute for Health and Care Research (NIHR) Health Protection Research Unit in Vaccines and Immunisation (NIHR200929/NIHR207408).