Failure to attend hospital appointments has a detrimental impact on care quality. Documented efforts to address this challenge have only modestly decreased no-show rates. Behavioral economics theory has suggested that more effective messages may lead to increased responsiveness. In complex, real-world settings, it has proven difficult to predict the optimal message composition. In this study, we aimed to systematically compare the effects of several pre-appointment message formats on no-show rates. We randomly assigned members from Clalit Health Services (CHS), the largest payer-provider healthcare organization in Israel, who had scheduled outpatient clinic appointments in 14 CHS hospitals, to one of nine groups. Each individual received a pre-appointment SMS text reminder five days before the appointment, which differed by group. No-show and advanced cancellation rates were compared between the eight alternative messages, with the previously used generic message serving as the control. There were 161,587 CHS members who received pre-appointment reminder messages who were included in this study. Five message frames significantly differed from the control group. Members who received a reminder designed to evoke emotional guilt had a no-show rates of 14.2%, compared with 21.1% in the control group (odds ratio [OR]: 0.69, 95% confidence interval [CI]: 0.67, 0.76), and an advanced cancellation rate of 26.3% compared with 17.2% in the control group (OR: 1.2, 95% CI: 1.19, 1.21). Four additional reminder formats demonstrated significantly improved impact on no-show rates, compared to the control, though not as effective as the best performing message format. Carefully selecting the narrative of pre-appointment SMS reminders can lead to a marked decrease in no-show rates. The process of a/b testing, selecting, and adopting optimal messages is a practical example of implementing the learning healthcare system paradigm, which could prevent up to one-third of the 352,000 annually unattended appointments in Israel.