OBJECTIVE: To describe the Vaccine Safety Datalink (VSD) project’s experience with population-based, active surveillance for vaccine safety and draw lessons that may be useful for similar efforts. PATIENTS AND METHODS: The VSD comprises a population of 9.2 million people annually in 8 geographically diverse US health care organizations. Data on vaccinations and diagnoses are updated and extracted weekly. The safety of 5 vaccines was monitored, each with 5 to 7 prespecified outcomes. With sequential analytic methods, the number of cases of each outcome was compared with the number of cases observed in a comparison group or the number expected on the basis of background rates. If the test statistic exceeded a threshold, it was a signal of a possible vaccine-safety problem. Signals were investigated by using temporal scan statistics and analyses such as logistic regression. RESULTS: Ten signals appeared over 3 years of surveillance: 1 signal was reported to external stakeholders and ultimately led to a change in national vaccination policy, and 9 signals were found to be spurious after rigorous internal investigation. Causes of spurious signals included imprecision in estimated background rates, changes in true incidence or coding over time, other confounding, inappropriate comparison groups, miscoding of outcomes in electronic medical records, and chance. In the absence of signals, estimates of adverse-event rates, relative risks, and attributable risks from up-to-date VSD data have provided rapid assessment of vaccine safety to policy-makers when concerns about a specific vaccine have arisen elsewhere. CONCLUSIONS: Care with data quality, outcome definitions, comparison groups, and length of surveillance are required to enable detection of true safety problems while minimizing false signals. Some causes of false signals in the VSD system were preventable and have been corrected, whereas others will be unavoidable in any active surveillance system. Temporal scan statistics, analyses to control for confounding, and chart review are indispensable tools in signal investigation. The VSD’s experience may inform new systems for active safety surveillance.