Background: Global differences in the Covid-19 death toll between various countries are still a matter of debate. We evaluated the potential influence of general burden of infectious diseases prior to the onset of the Covid-19 pandemic on the number of Covid-19 deaths during the pandemic. Methods: We used publicly available data from Worldometer and Our World in Data. In a complete case analysis, 178 countries and territories, where all parameters were available, entered the analysis, re-presenting 99.02% of the global population. Relationships between various parameters of the local burden of infectious diseases as well as childhood mortality, median age, and vaccination as independent variables, on Covid-19 deaths as the dependent variable, were evaluated. Results: Death from diarrheal disease, respiratory disease, pneumonia, pneumonia in childhood, malaria, and HIV, as well as childhood mortality correlated negatively with number of Covid-19 deaths (Spearman rank correlation test: p < 0.0001 for each parameter), while median age was positively correlated with Covid-19 deaths (p < 0.0001). In a multivariable approach using kernel functions, death from respiratory disease and median age retained statistical significance. When vaccination rate and median age were si-multaneously taken into account, vaccination rate showed a significant negative correlation with Covid-19 deaths. Conclusions: Local burden of infectious diseases as well as childhood mortality prior to the onset of the pandemic have a strikingly negative impact on Covid-19 deaths. This effect might be due to an increase in trained immunity and to the overall younger population. Vaccination appears as an effective preventive measure. (c) 2022 The Author(s). Published by Elsevier Ltd on behalf of King Saud Bin Abdulaziz University for Health Sciences. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/li-censes/by-nc-nd/4.0/).