Methadone-maintenance treatment clinics are strategically appealing sites for provision of directly administered antiretroviral therapy (DAART) to human immunodeficiency virus type 1 (HIV-1)-infected injection drug users (IDUs). We initiated an ongoing DAART protocol at a university-associated methadone clinic in April 2001, which continues to enroll participants. Participants ingested antiretroviral medications under direct supervision on days they attended the clinic; evening doses and doses on "methadone take-home days" were self-administered. Comparison IDUs receiving either standard care or treatment-adherence support were randomly selected from the population of the HIV-1 clinic where DAART participants received their primary care for HIV-1 infection, with frequency matching by sex, prior antiretroviral exposure, and receipt of methadone therapy. In an intention-to-treat analysis, 79% of DAART participants achieved HIV-1 RNA levels of <400 copies/mL by month 6 of therapy, compared with 54% in the standard care group (P=.035) and 48% in the adherence support group (P=.008). The preliminary results of this study both suggest that DAART can be feasible and acceptable to patients in a methadone clinic setting and provide impetus for further study of this treatment strategy in randomized controlled trials.