Although randomized clinical trials (RCTs) offer the highest level of scientific evidence, they are unable to evaluate the impact of treatments in the routine clinical practice. The heterogeneity of socio-demographic and clinical characteristics of patients, as well as the complexity of treatments, explain the gap between the effect observed in RCTs and its impact in the real-world setting. As compared to conventional trials, pragmatic RCTs are conducted in a setting as similar as possible to that of clinical practice, but they are not always able to narrow this gap. For this reasons, methods aimed to produce evidence on the impact of healthcare pathways in the real-world (i.e., real-world evidence) are of growing interest. In particular, those based on the Electronic Healthcare Utilization (EHU), including administrative databases on the healthcare services provided to beneficiaries of the National Health System, are receiving increasing consideration from both the scientific community and healthcare decision-makers. In this article, we described characteristics and research areas where EHU databases may be particularly useful, along with strengths and limits of this approach. In conclusion, EHU data should not replace RCTs, but they represent a powerful tool for integrating RCTs and for supporting healthcare decision-makers.