Background: Mutations started to accumulate in SARS-CoV-2 due to replication errors leading to emergence of variants. New variant appeared in December 2020. Caspase-8 can process pro-IL-1 and IL-18 causing the release of bioactive cytokines through immunogenic cell death that can kill virus-infected cells and activate the innate and adaptive immune systems. Objective: This study aimed tofind the relationship between caspase-8 levels and wild-type, alpha, beta or gamma and omicron variants and its correlation with severity, CRP, and WBC. Materials and methods:  134 nasal swabs and blood samples were collected from COVID-19 patients and 48 healthy individuals. RNA was extracted and rRT-PCR assay to detect variants using a special kit. Caspase-8 levels were determined by ELISA. Results: There was a significant relationship (p < /em> < 0.001) in patients median caspase-8 than in control. Logistic regression analysis showed that odds ratio (OR) of unadjusted patients was 4.33 and with age-adjusted was 7.24. Caspase-8 levels showed a significant relationship with the severity of infection by COVID-19 (p < /em> < 0.01) and highly significant relation with variants of SARS-CoV-2 (p < /em> < 0.0001), as follows: Alpha, wild type, beta or gamma and omicron. Caspase-8 levels were significantly increased with increase of CRP levels (p < 0.05) making both of them good prognostic markers for infection progress. Observed negative Spearman correlation (rs = -0.27; p < /em> < 0. 01) were detected between caspase-8 and WBC. Conclusion: The most severe infections with SARS-CoV-2 appeared in wild type and alpha variant. Caspase-8 and CRP are excellent biomarkers for the progression of infection.