Systematic reviews should incorporate as much relevant evidence as possible to reduce bias and research waste and increase reliability of results. Clinical trials registers are a key resource for identifying potentially eligible studies, particularly those that are unpublished, and therefore searching these registers is mandated for best practice systematic reviews. However, the process of searching can be challenging and no clear and consistent guidance on how best to do this exists. This paper provides step-by-step guidance on how to conduct systematic searches for studies using clinical trials registers, with a case study to illustrate each step. The guidance encompasses where to search and how to formulate the search strategy, conduct the search, download results, screen records, obtain data, update searches, and report on these searches.