OBJECTIVE: To assess the efficacy of a couple-based intervention to improve medication-taking behavior in a clinic population with demonstrated adherence problems. Design: A randomized controlled trial (SMART Couples Study) conducted between August 2000 and January 2004. SETTING: Two HIV/AIDS outpatient clinics in New York City. PARTICIPANTS: Heterosexual and homosexual HIV-serodiscordant couples (n = 215) in which the HIV-seropositive partner had 80%, > 90%, or > 95%) when compared with controls. However, in most cases, effects diminished with time, as seen at follow-up at 3 and 6 months. CONCLUSION: The SMART Couples program significantly improved medication adherence over usual care, although the level of improved adherence, for many participants, was still suboptimal and the effect was attenuated over time.