This study was conducted in health facilities in the capitals of five sub-Saharan African countries (Cotonou, Benin; Bangui, Central African Republic; Libreville, Gabon; Yaoundé, Cameroon; and Casablanca, Morocco). The purpose was to investigate factors promoting and impeding compliance with antiretroviral therapy (ART) and cotrimoxazole (CTX) prophylaxis in adult patients. Patients were interviewed immediately after follow-up examination to identify the problems that they encountered and the solutions that they proposed to improve compliance. Compliance was assessed based on three measurement modalities, i.e. skipping medication during the four days prior to attendance, counting the number of remaining tablets, and attendance assiduity. Compliance scores varied according to measurement modality from 65% to 90%. All patients underlined the impact of treatment on their daily life and the difficulty of following the prescribed regimen properly. Impeding factors for compliance were treatment-related hunger, lack of information, out-of-pocket expenses (including laboratory tests, transportation, and loss of income), side effects, long waiting time at the treatment centers, and fear stigma and discrimination. Efforts to increase access to treatment can only be successful if accompanied by measures to promote compliance.