The retention of persons on an HIV programme has been a global challenge. The success of any strategy to optimize adherence to anti-retroviral therapy (ART) depends on the intensive and effective adherence counselling and strategies. It is important to research whether persons receiving anti-retroviral therapy in public hospitals in Ghana are receiving the needed service that would optimize their adherence to the anti-retroviral therapy. Therefore, this study explored and described the experiences of healthcare professionals providing care, support and guidance to persons on ART at public hospitals in Ghana, as well as the best-practice guideline that could contribute to facilitating the ART adherence of patients. This study also explored and described the experiences of persons living with Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome (HIV/AIDS) on ART, regarding their adherence to the therapy. The study was organized into three phases. In Phase One: a qualitative, exploratory, descriptive and contextual design was employed. The research population included healthcare professionals, providing services at the HIV clinic at the public hospitals in Ghana, namely the Korle-Bu Teaching Hospital; the 37 Military Hospital and the Ridge Hospital. The healthcare professionals comprised of doctors, nurses, pharmacists and trained counsellors employed in any of the three public hospitals. Persons receiving ART at any of the three public hospitals were also part of the research population. Semi-structured interviews were conducted with healthcare professionals and persons receiving ART. Data were collected from healthcare professionals in relation to their experiences regarding the provision of ART services, their understanding of evidence-based practice and best-practice guidelines, as well as data on the experiences of persons receiving ART in relation to their adherence to the therapy. The data were analysed using Creswell’s six steps of data analysis; and the coding of the data was done according to Tesch’s eight steps of coding. Trustworthiness was ensured by using Lincoln and Guba’s framework which comprised credibility, transferability, dependability, confirmability and authenticity. Ethical principles such as beneficence and non-maleficence, respect for human dignity, justice, veracity, privacy and confidentiality were considered in the study. In phase two, the literature was searched by using an integrative literature review approach and critically appraising the methodological quality of the guidelines in order to identify the best available evidence related to adherence to ART. In Phase Three, a best-practice guideline for facilitating adherence to ART was developed for public hospitals in Ghana based on the findings of the empirical research of Phase One and the integrative literature review in Phase Two. The guideline was submitted to an expert panel for review; and it was modified, according to the recommendations of the panel.