Background: Coronavirus disease 2019 (COVID-19) has rapid spread worldwide and its pathogenesis is still not well understood. It's critical to identify the key immune inflammatory markers that may be correlated with COVID-19 severity. This study aimed to study the association of the peripheral lymphocyte subsets alteration and IL-6 serum level with disease severity and outcome in COVID-19. Methods: Samples from 30 COVID-19 patients were collected; one is EDTA anticoagulated for flowcytometric analysis of different lymphocyte subsets and the other for Interleukin-6 (IL6) serum level assessed by ELISA technique. Results: Absolute lymphocytic count (0.9 (0.5 - 1.4)× 10³/µL) , CD4⁺ T cells (217 (135.6 - 445.5) cells/µL) , CD8⁺ T cells (160 (112 - 338) cells/µL) and natural killer (NK) cells (33.3 (18.2 - 99.5) cells/µL)  were significantly reduced in severe COVID-19 patients with significantly elevated IL-6 serum levels 90 (70-120) (pg/mL) in severe patients. Lower T lymphocytes and NK subset counts with higher IL-6 levels were significantly associated with higher mortality. However, B cell count was not associated with severity or mortality. Il-6 levels, CD4⁺ and CD8⁺ T cells counts were considered best predictors of disease severity and mortality according to ROC curve analysis (with AUC 0.842, 0.884 and 0.773 respectively). Conclusion:Peripheral lymphocyte subsets as CD4⁺ T cells, CD8⁺ T cells and NK cells were significantly reduced in severe COVID-19 patients. CD4⁺ T cell count was the most significant biomarker for disease severity .Serum IL-6 levels were higher in severe illness. So, IL-6 can serve as a significant predictor of COVID-19 severity. As regard mortality and relation with lymphocytic count and lymphocytic subsets, total lymphocytic count and all T lymphocyte subsets CD4⁺, CD8⁺ and CD56⁺ cells count can be used as a significant predictor of death in COVID-19 patients. However, CD19⁺ cells counts had no relation with death.