BACKGROUND: The World Health Organization has prioritized the use of new technologies to assist in health care delivery in resource-limited settings. Findings suggest that the use of SMS on mobile phones is an advantageous application in health care delivery, especially in communities with an increasing use of this device. OBJECTIVE: The main aim of this trial is to assess whether sending weekly motivational text messages (SMS) through mobile phones versus no text messaging will improve retention in care and promote adherence to treatment and health outcomes among patients receiving HIV treatment in Fako Division of Cameroon. METHODS: This is a multisite randomized controlled single-blinded trial. Computer-generated random block sizes shall be used to produce a randomization list. Participants shall be randomly allocated into the intervention and control groups determined by serially numbered sealed opaque envelopes. The 156 participants will either receive the mobile phone text message or usual standard of care. We hypothesize that sending weekly motivational SMS reminders will produce a change in behavior to enhance retention; treatment adherence; and, hence, health outcomes. Participants shall be evaluated and data collected at baseline and then at 2, 4, and 6 months after the launch of the intervention. Text messages shall be sent out, and the delivery will be recorded. Primary outcome measures are retention in care and adherence to treatment. Secondary outcomes are clinical (weight, body mass index), biological (virologic suppression, tuberculosis coinfection), quality of life, treatment discontinuation, and mortality. The analysis shall be by intention-to-treat. Analysis of covariates shall be performed to determine factors influencing outcomes. RESULTS: Recruitment and random allocation are complete; 160 participants were allocated into 3 groups (52 in the single SMS, 55 in the double SMS, and 53 in the control). Data collection and analysis are ongoing, and statistical results will be available by the end of August 2019. CONCLUSIONS: The interventions will contribute to an improved understanding of which intervention types can be feasible in improving retention in care and promoting adherence to antiretroviral therapy. TRIAL REGISTRATION: Pan African Clinical Trial Registry in South Africa PACTR201802003035922; https://pactr.samrc.ac.za/TrialDisplay.aspx?TrialID=3035. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/15680.