Objectives. To assess the effectiveness of Short Message Service (SMS) reminder messages on antiretroviral and cotrimoxazole prophylaxis adherence among HIV-positive youths as well as the relative effectiveness of SMS with and without a response option.Methods. Eligible HIV-positive patients aged 15 to 22 years at 2 HIV clinics in Kampala, Uganda, participated in a year-long parallel individual-randomized controlled trial and were assigned in a 1-to-1-to-1 ratio to a weekly SMS message group, weekly SMS message with response option group, or a usual-care control group.Results. We enrolled 332 participants. Electronically measured mean adherence was 67\% in the control group, 64\% in the 1-way SMS group (95\% confidence interval [CI] = 0.77, 1.14), and 61\% in the 2-way SMS group (95\% CI = 0.75, 1.12) in an intent-to-treat analysis. Results for secondary outcomes and complete-case analysis were similarly statistically insignificant across groups.Conclusions. Despite previous evidence that interventions using SMS reminders can promote antiretroviral therapy adherence, this study shows that they are not always effective in achieving behavior change. More research is needed to find out for whom, and under what conditions, they can be beneficial.Trial registration. ClinicalTrials.gov identifier: NCT00830622.