Background Despite several publications covering patients from multiple centers, no international registry covered all patients with red blood cell diseases (RBCD) affected by COVID-19. The ERN-EuroBloodNet’s registry provided real-time registration of SARS-CoV-2 patients with RBCD, promoting timely disease-specific knowledge sharing during the pandemic’s early stages. Procedures The study evaluated patient distribution, the infection across different RBBDs, and severity risk factors across similar healthcare systems, using data collected from the ERN-EuroBloodNet’s REDCap platform. Results From April 2020 to April 2023, 681 infections were recorded among 663 patients, of which 373 had transfusion-dependent thalassemia or non-transfusion-dependent thalassemia (TDT/NTDT), and 269 had sickle cell disease (SCD). SCD patients had a higher incidence of COVID-19 than those with TDT/NTDT (10.5 vs. 4.8 COVID/100 patients). Notably, 92% of the cases were mild, with neither age nor the specific RBCD affecting severity. The number of comorbidities, notably obesity and hypertension, that patients had prior to infection was associated with more severe COVID-19. During the infection, the presence of vaso-occlusive crises, acute chest syndrome, kidney failure, and ground-glass opacities on chest tomography scans were associated with a more severe clinical picture. The vaccination rate (32%) mirrored that of the general population and showed a protective effect against severe COVID-19. The observed mortality rate was 0.7%, aligning with Europe’s general population. Conclusion: SARS-CoV-2 infection in SCD and TDT/NTDT patients is mild and without higher mortality than the general population. The ERN-Eurobloodnet’s registry collaborative structure exemplifies the power of international cooperation in tackling rare diseases, especially during health emergencies