AIM: The aim of this study was to examine the acceptability and efficacy of interactive short message service (SMS) in improving medication adherence in antiretroviral treatment (ART)-naïve individuals living with HIV/AIDS in Hengyang, Hunan, China. BACKGROUND: SMS via mobile phone has emerged as a potential tool for improving ART adherence. However, most studies used SMS only as a medication reminder, with few studies exploring the effect of comprehensive, interactive SMS. PATIENTS AND METHODS: In a randomized controlled trial, 100 HIV-positive patients on ART for <3 months were randomized into control or intervention arm. Participants in the control group received routine standard instruction for ART medication in the HIV clinics, while the intervention group received 6 months of an SMS intervention in addition to the standard care. A total of 124 text messages within 6 modules were edited, preinstalled, and sent to participants according to personalized schedules. Knowledge (of HIV and HIV medications), self-reported antiretroviral adherence (Visual Analog Scale [VAS] and Community Programs for Clinical Research on AIDS [CPCRA] Antiretroviral Medication Self-Report), and CD4 count were assessed at baseline and immediate post-intervention. Intervention participants were interviewed after completion of the study about their satisfaction with and acceptability of the SMS intervention. RESULTS: Baseline assessments were comparable between arms. Repeated-measures analysis showed that both HIV-related and ART medication knowledge of the intervention group showed better improvement over time than those of the control group after the intervention (<0.0001). For the adherence measures, compared with the control group, participants in the intervention group had significantly higher VAS mean score (=2.735, =0.006) and lower suboptimal adherence rate (=2.208, =0.027) at the end of the study. The intervention had no effect on CD4 cell count. Almost all (96%) intervention participants reported satisfaction or high satisfaction with the SMS intervention, with 74% desiring to continue to receive the SMS intervention. The preferred frequency of messages was 1-2 messages per week. CONCLUSION: An interactive SMS intervention with comprehensive content shows promising efficacy in promoting medication adherence in ART-naïve individuals. Future work might further refine its ability to optimally tailor the intervention for individual preferences.