Background and aims: The reduced fucosylation in the spike glycoprotein of SARS-CoV-2 and the IgG antibody has been observed in COVID-19. However, the clinical relevance of α-L-fucosidase, the enzyme for defucosylation has not been discovered. Materials and methods: 585 COVID-19 patients were included to analyze the correlations of α-L-fucosidase activity with the nucleic acid test, IgM/IgG, comorbidities, and disease progression. Results: Among the COVID-19 patients, 5.75% were double-negative for nucleic acid and antibodies. All of them had increased α-L-fucosidase, while only one had abnormal serum amyloid A (SAA) and C-reactive protein (CRP). The abnormal rate of α-L-fucosidase was 81.82% before the presence of IgM, 100% in the presence of IgM, and 66.2% in the presence of IgG. 73.42% of patients with glucometabolic disorders had increased α-L-fucosidase activity and had the highest mortality of 6.33%. The increased α-L-fucosidase was observed in 55.8% of non-severe cases and 72.9% of severe cases, with an odds ratio of 2.118. The α-L-fucosidase mRNA was irrelevant to its serum activity. Conclusion: The change in α-L-fucosidase activity in COVID-19 preceded the IgM and SAA and showed a preferable relation with glucometabolic disorders, which may be conducive to virus invasion or invoke an immune response against SARS-CoV-2. © 2021 Elsevier B.V.