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The SARS-CoV-2 (COVID-19) coronavirus pandemic has represented an emergency not only from a clinical point of view, but also for the environment due to the largely increased waste disposal. This study aimed at estimating, in the context of current trends, the increase in healthcare waste (HW) generation during the outbreak, based on data from a tertiary hospital. From the purveying office statements of 'SS Antonio e Biagio e Cesare Arrigo' Hospital of Alessandria (Italy), monthly HW generation data from January 2015 to March 2021 were retrospectively retrieved. Trends and COVID's impact were evaluated by Interrupted Time Series (ITS) design with linear regression models. Locally Weighted Scatterplot Smoothing was used to model the relation between infectious HW generation and proportion of COVID-related bed days. HW generation rose from 35.9 ± 3.8 tonnes month -1 (2.4 ± 0.2 kg per patient-day, kg PD -1 ) in 2015-2019, to 46.3 ± 6.0 tonnes month -1 (3.3 ± 0.7 kg PD -1 ) during the outbreak. The increasing trend was not appreciably modified as for its slope (p = 0.363), while a significant level change was found between baseline and outbreak (+ 0.72 kg PD -1 , p < 0.001). The proportion of COVID-related bed days non-linearly affected the infectious HW generated per patient-day, with steeper increases for proportions above 20%. The study showed a significant rise in HW generation in 2020-2021, reasonably due to the COVID outbreak; in addition, the generally increasing trend was not affected. Therefore, urgent measures are needed to conciliate safety requirements with HW generation issues.