Abstract: Internal and Emergency Medicine https://doi.org/10.1007/s11739-022-03054-1 IM-ORIGINAL To clarify the safety profile of paracetamol for home‑care patients with COVID‑19: a real‑world cohort study, with nested case–control analysis, in primary care Francesco Lapi1 · Ettore Marconi1 · Ignazio Grattagliano2 · Alessandro Rossi2 · Diego Fornasari3 · Alberto Magni2 · Pierangelo Lora Aprile2 · Claudio Cricelli2 Received: 3 June 2022 / Accepted: 11 July 2022 © The Author(s), under exclusive licence to Società Italiana di Medicina Interna (SIMI) 2022 Abstract Background and objective This study aimed to compare the prescribing patterns of paracetamol in COVID-19 with those for similar respiratory conditions and investigated the association between paracetamol use and COVID-19-related hospitalization/death. Methods Using a primary care data source, we conducted a cohort study to calculate the incidence rate of paracetamol use in COVID-19 and for similar respiratory conditions in 2020 and 2019 (i.e. pre-pandemic phase), respectively. In the study cohort, we nested a case–control analyses to investigate the association between paracetamol use and COVID-19-related hospitalizations/deaths. Results Overall, 1554 (33.4 per 1000) and 2566 patients (78.3 per 1000) were newly prescribed with paracetamol to treat COVID-19 or other respiratory conditions, respectively. Those aged 35–44 showed the highest prevalence rate (44.7 or 99.0 per 1000), while the oldest category reported the lowest value (17.8 or 39.8 per 1000). There was no association for early (OR = 1.15; 95% CI: 0.92–1.43) or mid-term (OR = 1.29; 95% CI: 0.61–2.73) users of paracetamol vs. non-users. Instead, the late users of paracetamol showed a statistically significant increased risk of hospitalization/death (OR = 1.75; 95% CI: 1.4–2.2). Conclusions Our findings provide reassuring evidence on the use and safety profile of paracetamol to treat early symptoms of COVID-19 as in other respiratory infections. Keywords Paracetamol · Prescribing pattern · Safety profile · Home-care · COVID-19 Background The SARS-CoV-2 pandemic is still burdening the healthcare system of several Western countries. Patients with mild-tomoderate COVID-19, for whom home-care treatment is requested, generally present flu-like symptoms such as fever, * Francesco Lapi lapi.francesco@simg.it 1 Health Search, Italian College of General Practitioners and Primary Care, Via del Sansovino 179, 50142 Florence, Italy 2 Italian College of General Practitioners and Primary Care, Florence, Italy 3 Department Medical Biotechnology and Translational Medicine, Università Degli Studi Di Milano, Milan, Italy pharyngitis, cough, rhinitis, headache, and myalgia [1, 2]. Among the available medications, paracetamol is recommended by the World Health Organization (WHO) [3], the National Institute for Health and Care Excellence (NICE) [4] as well as other regulatory agencies [5, 6] and scientific societies [7] among the mainstays to manage coronavirusrelated early symptoms. Nevertheless, there was conflicting and misleading communication [8, 9] on the pharmacotherapy for the home care of COVID-19. Some clinicians and researchers raised concerns on the safety profile of paracetamol when used in SARS-CoV-2 infections [10, 11]. They underlined that the potential depletion of glutathione (GSH) induced by paracetamol may even favour the pulmonary endothelium damages by SARS-CoV-2 [10, 12]. The authors therefore recommended to avoid the..