Here, one hundred patients (50 smokers and 50 non-smokers) clinically diagnosed with COVID-19 were studied. Yet, bioinformatics was used to predict epitopes on Tobacco mosaic virus coat protein (TMV-CP) to produce antibodies towards SARS-CoV-2. Death was three times higher in non-smokers than in smokers. However, biochemical parameters did not separate the groups. Bioinformatics analysis predicted the presence of B-cell epitopes in TMV-CP, suggesting the production of antibodies anti-TMV-CP in smoker patients. Smokers may develop severe forms of COVID-19, but survival was superior in the evaluated group than in non-smokers. Anti-TMV-CP antibodies, potentially present in smokers, might act as a pro-immune agent against SARS-CoV-2 at earlier stages of infection. These data are helpful for future studies assessing COVID-19 in smokers.