Introduction: We reviewed and compared current drug shortages and shortage management practices in six selected countries (Hungary, Belgium, Spain, Switzerland, Australia, United States) based on the most comprehensive national shortage databases for each country, for four Anatomical Therapeutic Chemical (ATC) groups, to analyze the criticality of drug shortages across countries and identify best practices in shortage management strategies. Materials and Methods: Countries were selected to cover a wide geographical range of high-income nations where a lack of economic power as a potential source of drug shortages is not observable. ATC groups were selected based on a pre-examination of the databases to analyze groups most often in shortage, and groups where the absence of which could have a severe negative impact on treatment outcomes. The bias originating from the different reporting systems had to be reduced to gain comprehensive and comparable information. The first bias-reducing mechanism was transforming the raw number of shortages into proportion per million people. Secondly, critical cases were classified, and thirdly, critical cases were compared with the Word Health Organization (WHO) Essential Medicine Lists. Results: The results indicate that every European country studied reports significantly higher total and critical shortages per population compared to the US and Australia. Within Europe, Hungary reports the highest number of cases both for total and critical shortages, while Spain has the lowest results in both aspects. While in the US and Australia critical shortages were observable in similar proportions across all ATC groups, in European countries ATC groups of anti-infectives for systemic use (J) and the nervous system (N) were found to account for a notably higher proportion of critical shortages. Current shortage management practices were examined in each country and classified into five groups to identify common best practices. Conclusions: Due to the different characterization of reporting systems, several bias-reducing mechanisms should be applied to compare and evaluate shortages. In addition, European harmonization should be initiated to create mutually acknowledged definitions and reporting systems, which could be the basis of good drug shortage handling practices in Europe.