OBJECTIVES: In a pandemic, medicine shortages are likely to increase due to disruptions in the supply chain and raising demand. The study aimed to investigate shortages of medicines to address COVID-19 related symptoms during the first wave of the pandemic in 2020 and the fourth wave in Q4/2021. *** METHODS: The study was conducted in Austria, Italy and Spain: the two latter were hit hard in the first wave, while Austria experienced a strong fourth wave in autumn 2021. Shortages were surveyed based on the reports to the publicly accessible shortages registers in the three countries, with a view to identify whether, or not, a shortage had been notified for February 2020, March 2020, April 2020 and November 2021. The search was conducted for 487 active substances which included medicines listed as therapy options to address COVID-19 symptoms in national and international guidelines and all further active substances of the same chemical subgroup (ATC-4 level). *** RESULTS: For 49 of the 487 reviewed active substances a shortage was notified for at least one of the study months, mostly March and April 2020. Thirty of these 49 active substances in short supply were explicitly recommended as COVID-19 therapy option. 69% of the active substances subject to a shortage notification concerned essential medicines in the WHO model list. During the first wave, the number of shortages in the defined product sample, both in terms of active substances as well shortage notifications, was higher in Spain and Italy compared to Austria. In November 2021 the number of active substances reported to be in short supply in Italy was similar to March / April 2020 data, while in Austria and Spain the data were aligned to respective February 2020 figures. *** DISCUSSION: The study showed an increase in shortages for COVID-19 relevant medicines in the first months of the pandemic. The Austrian and Italian registers, which report causes of the shortages, confirmed increased need as well as disruptions in manufacturing and distribution as reasons. For the first wave, data for Austria present lower numbers of shortages compared to Italy and Spain and an increase at a later stage. This may be attributable to the epidemiological situation since Austria was hit to a lesser extent in the first wave. Furthermore, Austria introduced mandatory reporting of shortages only in April 2020 which may also explain differences in data. An in-depth analysis was limited since additional explanatory factors (e.g. causes, mitigation measures) included in the national registers differ across the countries. Harmonisation of reporting requirements in the registers could help improve monitoring and managing the shortages.