ABSTRACT: BACKGROUND:Within systematic reviews, when searching for relevant references, it is advisable to use multiple databases. However, searching databases is laborious and time-consuming, as syntax of search strategies are database specific. We aimed to determine the optimal combination of databases needed to conduct efficient searches in systematic reviews and whether the current practice in published reviews is appropriate. While previous studies determined the coverage of databases, we analyzed the actual retrieval from the original searches for systematic reviews. METHODS:Since May 2013, the first author prospectively recorded results from systematic review searches that he performed at his institution. PubMed was used to identify systematic reviews published using our search strategy results. For each published systematic review, we extracted the references of the included studies. Using the prospectively recorded results and the studies included in the publications, we calculated recall, precision, and number needed to read for single databases and databases in combination. We assessed the frequency at which databases and combinations would achieve varying levels of recall (i.e., 95%). For a sample of 200 recently published systematic reviews, we calculated how many had used enough databases to ensure 95% recall. RESULTS:A total of 58 published systematic reviews were included, totaling 1746 relevant references identified by our database searches, while 84 included references had been retrieved by other search methods. Sixteen percent of the included references (291 articles) were only found in a single database; Embase produced the most unique references (n?=?132). The combination of Embase, MEDLINE, Web of Science Core Collection, and Google Scholar performed best, achieving an overall recall of 98.3 and 100% recall in 72% of systematic reviews. We estimate that 60% of published systematic reviews do not retrieve 95% of all available relevant references as many fail to search important databases. Other specialized databases, such as CINAHL or PsycINFO, add unique references to some reviews where the topic of the review is related to the focus of the database. CONCLUSIONS:Optimal searches in systematic reviews should search at least Embase, MEDLINE, Web of Science, and Google Scholar as a minimum requirement to guarantee adequate and efficient coverage.