Abstract Introduction Several studies have reported an unexpectedly low prevalence SERO of current smoking among hospitalized patients with Covid-19. However, these studies mostly compared observed to expected rates of smoking without direct comparison with individual controls. Objective To examine the association of nicotine-replacement therapy, as a surrogate of smoking, with hospitalization and all-cause mortality during the first wave of SARS-CoV-2 epidemic in France. Methods We conducted a nationwide matched exposed/unexposed cohort study using information from the French national health data system which covers the entire French population. We conducted two separate analyses, the first in individuals exposed to nicotine-replacement therapy without major smoking-related diseases MESHD (cancer, cardiovascular and/or respiratory diseases MESHD) and the second in those presenting these conditions. We included all individuals, aged TRANS between 18 and 75 years, who had been reimbursed at least one nicotine-replacement therapy between November 15, 2019, and February 15, 2020. For each exposed individual, we randomly selected, from the entire Metropolitan French population, up to two non-exposed individuals (1:2) matched for the following variables: age TRANS (same year of birth), sex, department of residence (n=96 in Metropolitan France), and complementary universal health insurance (CMU-C). The three end points were a hospitalization with Covid-19, a death MESHD or an intubation in hospitalized patients with Covid-19, and all-cause mortality. We compared outcomes in individuals who were exposed to nicotine-replacement therapy with those in individuals who were not, using a multivariable Cox model with inverse probability weighting according to the propensity score. Results In the first analysis, 297,070 individuals without major smoking-related diseases MESHD exposed to nicotine-replacement therapy were matched with 558,228 unexposed individuals without major smoking-related diseases MESHD. Individuals were aged TRANS on average 45.6 years (standard deviation: 12.7) and 48.8% were male TRANS. From February 15, 2020 to June 7, 2020, hospitalization with Covid-19 occurred in 647 patients (151 patients in the nicotine-replacement therapy group and 496 patients in the unexposed group). In the main multivariable analysis, nicotine-replacement therapy was associated with a decreased risk of hospitalization with Covid-19 compared with unexposed individuals (hazard ratio, 0.50; 95% CI, 0.41 to 0.61). Nicotine-replacement therapy exposure was also associated with a decreased risk of intubation or death MESHD in hospitalized individuals with Covid-19 (13 vs. 73 patients, hazard ratio, 0.31; 95% CI, 0.17 to 0.57) but with an increased risk of all-cause mortality (251 vs. 231 deaths MESHD, hazard ratio, 1.49; 95% CI, 1.24 to 1.80). In the second analysis, 128,768 individuals with major smoking-related diseases MESHD exposed to nicotine-replacement therapy were matched with 243,793 unexposed individuals. Individuals were aged TRANS on average 55.3 years (standard deviation: 11.4) and 53.3% were male TRANS. In the main multivariable analysis, nicotine-replacement therapy exposure was neither associated with risk of hospitalization with Covid-19 (240 patients in the nicotine-replacement therapy group and 398 patients in the unexposed group, hazard ratio, 1.13; 95% CI, 0.94 to 1.38) nor with risk of death MESHD or an intubation in hospitalized individuals with Covid-19 (48 vs. 61 patients, hazard ratio, 1.00; 95% CI, 0.65 to 1.54). All-cause mortality was higher in the nicotine-replacement therapy group (1040 vs. 366 deaths MESHD, hazard ratio, 3.83; 95% CI, 3.41 to 4.31). Conclusions This large-scale observational study suggests that smoking, measured by exposure to nicotine-replacement therapy, was associated with an increased risk of overall mortality during the first wave of SARS-CoV-2 epidemic in France, although it was associated with a lower risk of severe Covid-19 in individuals without major related-smoking diseases MESHD. Experimental and clinical studies are needed to disentangle the potential mechanisms of nicotine and/or smoking in Covid-19 risk. Whatever the nature of these associations, the global impact of smoking is harmful for health even over a short epidemic period.