Introduction: Tobacco smoking is the leading risk factor for many respiratory diseases, and current smokers have an increased risk of a worst clinical COVID-19 outcome. Several genes are associated with nicotine addiction. This research aimed to evaluate the association of the polymorphisms rs16969968 (CHRNA5) y rs3918396 (ADAM33) in patients who developed severe COVID-19. Methods: We included 917 COVID-19 patients hospitalized with critical disease and oxygenation impairment. They were divided into two groups, tobacco-smoking patients (n=257) and non-smokers (n=660). The genotype and allele frequencies of two single nucleotide variants, the rs16969968 (CHRNA5) and rs3918396 (ADAM33), were evaluated in both groups using real-time PCR. At admission to the hospital and between the seventh and tenth day of hospitalization, we collected several laboratory tests from the clinical record. Results: Genotype and allele analyses compared smokers vs. non-smokers patients; the codominant model shows no association between rs16969968 (CHRNA5) and rs3918396 (ADAM33). We analyzed the study population according to the rs16969968 genotype (GA + AA, n=180, and GG, n=737). At admission time, the erythrocyte sedimentation rate (ESR) shows statistical differences; the GA+AA group had higher values than the GG group (p = 0.038, 32 vs. 26 mm/h, respectively). The GA+AA group had a high positive correlation (p<0.001, rho=0.753) between fibrinogen and C-reactive protein. Conclusions: At the hospital admission, carriers of one or two copies of the risk allele in CHRNA5 (rs16969968/A) have high ERS and a positive correlation between fibrinogen and C-reactive protein.