BACKGROUND: The weaknesses of classical explanatory randomized controlled trials (RCTs) include limited generalizability, high cost, and time burden. Pragmatic RCTs nested within electronic health records (EHRs) can be useful to overcome such limitations. Serum lithium monitoring has often been underutilized in real-world practice in Japan. This trial aims to evaluate the effectiveness of the EHR-nested reminder system for serum lithium level monitoring in the maintenance of therapeutic lithium concentration and in the improvement of the quality of care for patients on lithium maintenance therapy. METHODS: The Kyoto Toyooka nested controlled trial of reminders (KONOTORI trial) is an EHR-nested, parallel-group, superiority, stratified, permuted block-randomized controlled trial. Screening, random allocation, reminder output, and outcome collection will be conducted automatically by the EHR-nested trial program. Patients with a mood disorder taking lithium carbonate for maintenance therapy will be randomly allocated to the two-step reminder system for serum lithium monitoring or to usual care. The primary outcome is the achievement of therapeutic serum lithium concentration between 0.4 and 1.0 mEq/L at 18 months after informed consent. DISCUSSION: The KONOTORI trial uses EHRs to enable the efficient conduct of a pragmatic trial of the reminder system for lithium monitoring. This may contribute to improved quality of care for patients on lithium maintenance therapy. TRIAL REGISTRATION: University Hospital Medical Information Network (UMIN) Clinical Trials Registry, UMIN000033633. Registered on 3 July 2018.