AbstractBackground Long-term adherence to prescription medications for the treatment of chronic disease remains low. While there are many contributors to suboptimal medication use, simple forgetfulness is widely believed to be central. Relatively simple devices may be a particularly cost-efficient and scalable way to promote adherence, however limited data exists about their ability to improve adherence in real-world settings. Methods/design The REMIND trial is a prospective, intent-to-treat randomized control trial to evaluate the impact on medication adherence of three simple, low-cost devices (Take-N-Slide™, the RxTimerCap™, and a standard pillbox). In March 2014, we enrolled 53,480 individuals 18 to 64 years old taking one to three medications to treat chronic disease whose prescription drug benefits were administered by CVS Caremark. The study's primary outcome is optimal adherence over the 12-month period after randomization. Using a randomization ratio of 1:2 between control and each intervention arm, the study has more than 80% power with an alpha of 5% to detect a 1% difference in the rate of optimal adherence between intervention and control groups and across intervention arms. Discussion The REMIND trial is the first randomized study to rigorously evaluate the impact of simple, low-cost reminder devices on medication adherence. The results will inform comparative cost effectiveness studies of reminder systems in improving medication adherence and clinical outcomes.