Abstract Background Options for patients to receive unauthorised medicines through compassionate use (CU) in Europe vary greatly. There are two CU pathways: cohort programmes, regulated uniformly by the Regulation across EU member states, and individual patient requests (IPRs) governed by the Directive. The latter allows member states to determine their own laws, resulting in heterogeneous regulatory requirements and challenges in operationalization. Consequently, patients may experience delays in accessing CU medicines depending on their country of residence. To compare CU availability across European countries and formulate recommendations for improvement, we analyzed 8,934 patient requests from 30 European countries. Methods An exploratory post-hoc analysis was conducted using pooled collaborative data from 8,934 patient requests provided by Merck KGaA, Novartis, Roche, and Sanofi, tracked from January 1, 2020 to April 30, 2023 across 30 countries. All requests with complete dates for submission, company approval, relevant Ethics Committees or Health Authorities, and shipment dates were included. Results While internal company CU approval steps were found to be similar with a median approval time of 5 days (median interquartile range (IQR) of 1 (0–6) for cohorts; median IQR 4 (1–8) for IPRs), the time from company approval until shipment varied between cohort requests (median IQR 5 (1–16) days) and IPRs (median IQR 8 (1–22) days). Challenges experienced included differences in the use of CU terminologies, scope, settings, regulatory, and operational requirements. Conclusion Our findings indicate that differing national requirements across Europe lead to operational challenges and inter-country variability in CU implementation posing operational challenges for stakeholders, highlighting the need for improved harmonization.