Randomized clinical trials provide the foundation of clinical evidence to guide physicians in their selection of treatment options. Importantly, randomization is the only reliable method to control for confounding factors when comparing treatment groups. However, randomized trials have limitations, including the increasingly prohibitive costs of conducting adequately powered studies. Local and national regulatory requirements, delays in approval, and unnecessary trial processes have led to increased costs and decreased efficiency. Another limitation is that clinical trials involve selected patients who are treated according to protocols that might not represent real-world practice. A possible solution is registry-based randomized clinical trials. By including a randomization module in a large inclusive clinical registry with unselected consecutive enrolment, the advantages of a prospective randomized trial can be combined with the strengths of a large-scale all-comers clinical registry. We believe that prospective registry-based randomized clinical trials are a powerful tool for conducting studies efficiently and cost-effectively.