BackgroundVaccination is the most effective strategy to prevent infectious diseases, yet vaccination coverage has not reached the target level. To promote vaccination uptake, digital health interventions (DHIs) have been used in various vaccination programs.ObjectiveThis study aimed to perform a systematic review of the cost-effectiveness analyses of DHIs for the improvement of the uptake of vaccination programs.MethodsA literature review was conducted in MEDLINE (Ovid), Embase (Ovid), APA PsycINFO (Ovid), Web of Science, Scopus, CINAHL Ultimate (EBSCOhost), Center for Review and Dissemination, and Institute for IEEE Xplore up to October 2022. Health economic evaluations that met the following inclusion criteria were included: (1) adult or pediatric vaccination programs; (2) interventions delivered through digital technology; (3) full-scale health economic analyses including cost-effectiveness, cost-utility, cost-benefit, or cost-consequence analyses; and (4) evaluations conducted by model-based or trial-based analyses. The quality of each included study was evaluated using the Consolidated Health Economic Evaluation Reporting Standards (CHEERS).ResultsThe systematic review included 7 studies. Four of the cost-effectiveness studies were conducted by model-based analyses, and 3 were trial-based analyses. One study reported the additional cost per quality-adjusted life years (QALYs) gained, whereas 6 studies reported the additional cost per individual vaccinated (or return case). The vaccines targeted the human papillomavirus (HPV) vaccine, influenza vaccination, measles-mumps-rubella (MMR) vaccine, and children immunization at different ages. The DHIs were delivered by television campaign, web-based decision aid, SMS text message, telephone, and computer-generated recall letters. The studies were classified as very good (n=5) and good (n=2) qualities. One study concluded that the DHI was cost-saving, and 6 studies concluded that the DHI was cost-effective.ConclusionsThis study is the first systematic review on cost-effectiveness analyses of DHIs to improve vaccination uptake. All included studies have good to very good quality on study assessment and reported the DHIs to be cost-saving or cost-effective in the improvement of vaccination uptake.