Early epidemiologic studies documented lower rates of active smokers compared to former or non-smokers in symptomatic patients affected by coronavirus disease 2019 (COVID-19). It was hypothesized that nicotine may interact with SARS-CoV-2 entry in human cells by downregulating the expression of angiotensin converting enzyme 2, and might mitigate the inflammatory response induced by the virus through activation of the nicotinic cholinergic system. This multicentre, randomized, double-blind, placebo-controlled trial aimed to determine the efficacy and safety of nicotine administered by a transdermal patch in critically ill patients with COVID-19 pneumonia who were receiving invasive mechanical ventilation. The results show that transdermal nicotine did not significantly reduce day-28 mortality. 60-Day mortality, time to successful extubation, days alive and free from mechanical ventilation, renal replacement therapy, vasopressor support or organ failure were also not modified by nicotine.