The study objectives were to determine the impact of the patient-clinician relationship on patient adherence to HIV medication, to identify which aspects of the patient-clinician relationship and the treatment system influenced adherence, and to determine which of these variables remained important when the impact of mental distress and substance abuse were considered. The design was a cross-sectional study using a sample of 120 HIV+ clinic patients. The Primary Care Assessment Survey (PCAS) assessed the clinician-patient relationship and the treatment system. The Composite International Diagnostic Inventory-Short Form (CIDI-SF) screened for mental disorders, and the Brief Substance Abuse History Form measured recent and remote substance use. Patient adherence was assessed using five markers including 3 interview-elicited self-reports, 1 medical chart review, and 1 summary score. Logistic regression analyses identified independent predictors of each adherence behavior. PCAS scores contributed to all five models, and their effects persisted when mental distress and substance abuse were considered. Adherence behaviors are explained by a variety of factors and should be assessed using multiple methods. Further study to illuminate the mechanisms of action of the clinician-patient relationship on adherence to HIV medication is warranted.