Introduction and ObjectiveSocial media has been proposed as a possibly useful data source for pharmacovigilance signal detection. This study primarily aimed to evaluate the performance of established statistical signal detection algorithms in Twitter/Facebook for a broad range of drugs and adverse events.MethodsPerformance was assessed using a reference set by Harpaz et al., consisting of 62 US Food and Drug Administration labelling changes, and an internal WEB-RADR reference set consisting of 200 validated safety signals. In total, 75 drugs were studied. Twitter/Facebook posts were retrieved for the period March 2012 to March 2015, and drugs/events were extracted from the posts. We retrieved 4.3 million and 2.0 million posts for the WEB-RADR and Harpaz drugs, respectively. Individual case reports were extracted from VigiBase for the same period. Disproportionality algorithms based on the Information Component or the Proportional Reporting Ratio and crude post/report counting were applied in Twitter/Facebook and VigiBase. Receiver operating characteristic curves were generated, and the relative timing of alerting was analysed.ResultsAcross all algorithms, the area under the receiver operating characteristic curve for Twitter/Facebook varied between 0.47 and 0.53 for the WEB-RADR reference set and between 0.48 and 0.53 for the Harpaz reference set. For VigiBase, the ranges were 0.64–0.69 and 0.55–0.67, respectively. In Twitter/Facebook, at best, 31 (16%) and four (6%) positive controls were detected prior to their index dates in the WEB-RADR and Harpaz references, respectively. In VigiBase, the corresponding numbers were 66 (33%) and 17 (27%).ConclusionsOur results clearly suggest that broad-ranging statistical signal detection in Twitter and Facebook, using currently available methods for adverse event recognition, performs poorly and cannot be recommended at the expense of other pharmacovigilance activities.Electronic supplementary materialThe online version of this article (10.1007/s40264-018-0699-2) contains supplementary material, which is available to authorized users.