Hypericum perforatum is a very popular traditional herbal medicine used for antidepressant effects. Hypericum perforatum herbal preparations can be the cause for pharmacokinetic interactions due to the possibility that components of the plant induce the activity of CYP3A4, CYP2B6, CYP2C9, CYP2C19 and P-glycoprotein. The aim of this study is to update the safety profile related with the use of Hypericum perforatum in European countries. An analysis was conducted on spontaneous reports of suspected adverse reactions (SARs) recorded in the EudraVigilance database. In addition, a disproportionality analysis was performed to compare SARs related to hepatobiliary disorders in patients exposed to Hypericum perforatum with those reported for the synthetic antidepressants fluoxetine and citalopram. Both drug interactions and hepatobiliary disorders were specifically assessed as adverse reactions associated with Hypericum perforatum in comparison to the reference drugs. Pharmacological interactions were the most frequent cause of SARs caused by Hypericum perforatum, while analysis of disproportionality showed that Hypericum perforatum was associated with a higher reporting probability of “Hepatobiliary disorders” and, although to a lesser extent, also “Drug interactions”, in comparison to fluoxetine and citalopram. Data from this research draws attention to the potential hepatotoxicity of Hypericum perforatum and suggests a deeper study of the causes, which appear to be only partially linked with the mechanisms that produce pharmacological interactions.