Advances in clinical therapies for people living with HIV have greatly increased life expectancies, but the high levels of adherence that are necessary for clinical success are infrequently achieved, especially for chronically homeless substance users. The Open Door is a harm reduction housing program that seeks to improve clinical outcomes for this population. We present findings from qualitative interviews with residents of the program, conducted to explore facilitators of residents’ success in the program, which is ultimately defined as HIV clinical adherence. Two major themes developed. Positive changes captures processes or characteristics that residents reported as having changed as a result of living in the program. Mechanisms of success reflects aspects of the program to which residents attributed their improved adherence. Given that improving adherence in vulnerable populations has both clinical and public health implications, our study suggests future avenues for research and foundations on which to build future interventions.