This paper describes the AACTG Adherence Instruments, which are comprised of two self-report questionnaires for use in clinical trials conducted by the Adult AIDS Clinical Trials Group (AACTG). The questionnaires were administered to 75 patients at ten AACTG sites in the USA. All patients were taking combination antiretroviral therapy (ART), including at least one protease inhibitor. Eleven per cent of patients reported missing at least one dose the day before the interview, and 17% reported missing at least one dose during the two days prior. The most common reasons for missing medications included 'simply forgot' (66%) and a number of factors often associated with improved health, including being busy (53%), away from home (57%) and changes in routine (51%). Less adherent patients reported lower adherence self-efficacy (p = 0.006) and were less sure of the link between non-adherence and the development of drug resistance (p = 0.009). They were also more likely to consume alcohol, to be employed outside the home for pay and to have enrolled in clinical trials to gain access to drugs (all p < 0.05). Twenty-two per cent of patients taking drugs requiring special instructions were unaware of these instructions. Each questionnaire took approximately ten minutes to complete. Responses to the questionnaires were favourable. These questionnaires have been included in six AACTG clinical trials to date and have been widely disseminated to investigators both in the USA and abroad.