Abstract Title: Exploring the Link Between Smoking and Short-Term Mortality in Hospitalized COVID-19 Patients: Insights from Population Data Background Smoking cigarettes represents a prevalent form of tobacco consumption, with cigarette smoke containing harmful substances like nicotine, tar, and various carcinogens, which contribute to a spectrum of health issues. This study extends the discussion of smoking in the context of the COVID-19 pandemic, where data suggests that non-smokers hospitalized with the COVID-19 virus are more vulnerable to complications. Methods To investigate the relationship between smoking history and short-term mortality among COVID-19 patients, publicly accessible deidentified statewide hospitalization records of individuals aged ≥18 from Q2 2020 to Q1 2022 in Texas were utilized. Identification of smokers was performed using ICD-10-CM codes F17200, Z8789, and U071. Three models were employed to assess this link: multilevel logistic regression with propensity adjustment, supported by alternative analyses including propensity score matching and multivariable logistic regression. Results Nicotine administration has been observed to increase nAChR7 expression and inhibit pro-inflammatory cytokines like TNF-α, IL-1, and IL-6, while stimulating anti-inflammatory cytokines such as IL-10. Moreover, nicotine's potential dual effect on ACE2 receptors—increasing expression while reducing available binding sites for the COVID-19 virus—has been highlighted. Additionally, nicotine has been shown to inhibit NF-κB, a critical transcription factor in the activation of inflammation in various immune cells, and as an agonist of α7nAChRs, it can reduce cytokine storm mediators such as HMGB1. Notably, smoking has been associated with reduced furin (PCSK3) levels. Conclusion In conclusion, nicotine, widely consumed as tobacco smoking and recognized as an addictive substance, may harbor therapeutic potential that necessitates further exploration. Analogous pharmacological agents with high addictive potential are presently utilized for therapeutic purposes with appropriate pharmaceutical protocols. Further research into nicotine's standard processing, therapeutic index, dosing, and other aspects is imperative. Despite the inherent limitations of retrospective studies, nicotine has demonstrated mortality benefits, underscoring the importance of further investigation through prospective studies.