Pharmacoepidemiology studies are an important complement to Randomized Clinical trials, but such studies face several challenges, such as confounding and selective reporting. How to best address confounding has been discussed in detail for many years. More recent discussions have highlighted the value of pharmacoepidemiology studies based on pre-registered protocols. This is an important step to address problems related to selective reporting and to enhance transparency and reproducibility. In this editorial perspective, we discuss the value of pre-registered protocols in pharmacoepidemiology.