| Summary: | We aimed to identify whether lymphopenia is a reliable prognostic marker for COVID-19. Using data derived from a Korean nationwide longitudinal cohort of 5628 COVID-19 patients, we identified propensity-matched cohorts (<i>n</i> = 770) with group I of severe lymphopenia (absolute lymphocyte counts [ALC]: <500/mm<sup>3</sup>, <i>n</i> = 110), group II of mild-to-moderate lymphopenia (ALC: ≥500–<1000/mm<sup>3</sup>, <i>n</i> = 330), and group III, no lymphopenia (ALC: ≥1000/mm<sup>3</sup>, <i>n</i> = 330). A significantly higher mortality rate was associated with lymphopenia severity: 40% in group I, 22.7% in group II, and 13.0% in group III (<i>p</i> < 0.001). At 28 days, the estimated inferior overall survival associated with intensified lymphopenia: 62.7% in group I, 79.9% in group II, and 89.0% in group III (<i>p</i> < 0.001). Lymphopenia contributed significantly toward a greater need for interventions in all groups but at varying degrees: requirements of invasive ventilation, intensive oxygen supply, or adequate oxygen supply, respectively (<i>p</i> < 0.001). The lymphopenia intensity was independently associated with higher COVID-19 mortality in multivariable analysis; adjusted odds ratios of 5.63 (95% CI, 3.0–10.72), and 2.47 (95% CI, 1.5–4.13) for group I and group II, respectively. Lymphopenia and its severity levels may serve as reliable predictive factors for COVID-19 clinical outcomes; thus, lymphopenia may provide the prognostic granularity required for clinical use in the management of patients with COVID-19.
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