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The prognostic role of immune cells in amyotrophic lateral sclerosis (ALS) remains undetermined. Therefore, we conducted a longitudinal cohort study including 288 ALS patients with up to 5-year follow-up during 2015-2020 recruited at the only tertiary referral center for ALS in Stockholm, Sweden, and measured the levels of differential leukocytes and lymphocyte subpopulations. The primary outcome was risk of death after diagnosis of ALS and the secondary outcomes included functional status and disease progression rate. Cox model was used to evaluate the associations between leukocytes and risk of death. Generalized estimating equation model was used to assess the correlation between leukocytes and functional status and disease progression rate. We found that leukocytes, neutrophils, and monocytes increased gradually over time since diagnosis and were negatively correlated with functional status, but not associated with risk of death or disease progression rate. For lymphocyte subpopulations, NK cells (HR = 0.61, 95% CI = [0.42-0.88] per SD increase) and Th2-diffrentiated CD4+ central memory T cells (HR= 0.64, 95% CI = [0.48-0.85] per SD increase) were negatively associated with risk of death, while CD4+ effector memory cells re-expressing CD45RA (EMRA) T cells (HR = 1.39, 95% CI = [1.01-1.92] per SD increase) and CD8+ T cells (HR= 1.38, 95% CI = [1.03-1.86] per SD increase) were positively associated with risk of death. None of the lymphocyte subpopulations was correlated with functional status or disease progression rate. Our findings suggest a dual role of immune cells in ALS prognosis, where neutrophils and monocytes primarily reflect functional status whereas NK cells and different T lymphocyte populations act as prognostic markers for survival. [ABSTRACT FROM AUTHOR]