Background: We implemented a text message-based Short Message Service computer-assisted self-interviewing (SMS-CASI) system to aid adherence and monitor behavior in MTN-017, a phase 2 safety and acceptability study of rectally-applied reduced-glycerin 1% tenofovir gel compared to oral emtricitabine/tenofovir disoproxil fumarate tablets. We sought to implement SMS-based daily reminders and product use reporting, in four countries and five languages, and centralize data management/automated-backup. Methods: We assessed features of five SMS programs against study criteria. After identifying the optimal program, we systematically implemented it in South Africa, Thailand, Peru, and the United States. The system consisted of four windows-based computers, a GSM dongle and sim card to send SMS. The SMS-CASI was, designed for 160 character SMS. Reminders and reporting sessions were initiated by date/time triggered messages. System, questions, responses, and instructions were triggered by predetermined key words. Results: There were 142,177 total messages: sent 86,349 (60.73%), received 55,573 (39.09%), failed 255 (0.18%). 6153 (4.33%) of the message were errors generated from either our SMS-CASI system or by participants. Implementation challenges included: high message costs; poor data access; slow data cleaning and analysis; difficulty reporting information to sites; a need for better participant privacy and data security; and mitigating variability in system performance across sites. We mitigated message costs and poor data access by federating the SMS-CASI system, and used secure email protocols to centralize data backup. We developed programming syntaxes to facilitate daily data cleaning and analysis, and a calendar template for reporting SMS behavior. Lastly, we ambiguated text message language to increase privacy, and standardized hardware and software across sites, minimizing operational variability. Conclusion: We identified factors that aid international implementation and operation of SMS-CASI for real-time adherence monitoring. The challenges and solutions we present can aid other researchers to develop and manage an international multilingual SMS-based adherence reminder and CASI system.