The evaluation of minimal clinically important difference (MCID) and minimal important difference (MID) has become central to regulatory and policy-making in health technology assessment (HTA). MCID refers to the smallest change in a patient-related outcome that a patient would identify as noticeable or perceivable. While institutions like the FDA and EMA increasingly emphasize MCID in evaluating patient-reported outcomes (PROs), challenges persist due to its inconsistent application and lack of standardization across countries and HTA bodies. For instance, Germany’s Institute for Quality and Efficiency in Health Care (IQWiG) employs a fixed ≥15% improvement threshold, but this has been contested due to variability in diseases, scales, and patient profiles. MCID plays a crucial role in both clinical trials and postmarket surveillance, as it helps determine whether observed improvements yield meaningful benefits for patients or not. However, a universal threshold has been criticized by many because of significant variations in baseline characteristics such as age, disease severity, comorbidities, treatment history, ethnicity, sociocultural status, or clinical context, among others. Consequently, some argue for an individualized approach that tailors MCID to specific conditions and populations. This method would consider factors like ethnicity, drug tolerance, disease progression over time, or even culture. Across global HTA systems, MCID’s implementation diverges. Agencies such as NICE in the United Kingdom and HAS in France differ significantly from IQWiG in Germany in their reliance on MCID. The use of real-world evidence (RWE), particularly in rare diseases and gene therapies, is emerging as a way to validate clinical trial results and complement MCID assessments. However, even within Europe, varying methodological standards and thresholds often lead to different reimbursement and approval outcomes for the same drug, as seen in the contrasting evaluations. The lack of consensus on how to calculate MCID—whether through anchor-based, distribution-based, or hybrid methods—further complicates its utility. Studies show inconsistent usage of MCID across specialties and tools, reflecting the absence of a robust methodological framework. This inconsistency impedes the comparability of research findings and policy decisions, especially in cost-effectiveness analysis (CEA), where MCID can clarify whether incremental clinical benefits justify additional costs. Recent regulatory efforts within the European Union aim to harmonize HTA procedures through initiatives like the EU HTA Regulation and Joint Clinical Assessments (JCA). These aim to reduce redundancy and facilitate timely access to innovative therapies. Still, disparities persist due to differences in political will, health-care infrastructure, and economic capacity, particularly in low- and middle-income countries. Therefore, while standardization could enhance comparability and meta-analyses, a flexible, patient-centered MCID approach remains crucial for accurate and equitable health-care decision-making.