Older people living with HIV (PLWH) are at increased risks of co-morbidities and polypharmacy. However, little is known about factors affecting their needs and concerns about medicines. This systematic review aims to describe these and to identify interventions to improve medicine optimisation outcomes in older PLWH. Multiple databases and grey literature were searched from inception to February 2022 including MEDLINE, CINAHL, PsycInfo, PsychArticles, the Cochrane Database of Systematic Reviews and the Cochrane Controlled Register of Trials, Abstracts in Social Gerontology, and Academic Search Complete. Studies reporting interventions/issues affecting older PLWH (sample populations with mean/median age ≥ 50 years; any aspect of medicine optimisation, or concerns). Quality assessments were completed by means of critical appraisal checklists for each study design. Title and abstract screening was led by one reviewer and a sample reviewed independently by two reviewers. Full-paper reviews were completed by one author and a 20% sample was reviewed independently by two reviewers. Data were extracted by three independent reviewers using standardised data extraction forms and synthesised according to outcomes or interventions reported. Data were summarised to include key themes, outcomes or concerns, and summary of intervention. Seventy-nine (n=79) studies met the eligibility criteria, most of which originated from the USA (n=36). A few studies originated from Australia (n=5), Canada (n=5), Spain (n=9), and the UK (n=5). Ten studies originated from Sub-Saharan Africa (Kenya n=1, South Africa n=6, Tanzania n=1, Uganda n=1, Zimbabwe n=1). The rest of the studies were from China (n=1), France (n=1), Germany (n=1), Italy (n=1), the Netherlands (n=1), Pakistan (n=1), Switzerland (n=1), Saudi Arabia (n=1) and Ukraine (n=1). Publication dates ranged from 2002 to 2022. Sample sizes ranged from 10 to 15,602 across studies. The factors affecting older PLWH's experience of and issues with medicines were co-morbidities, health-related quality of life, polypharmacy, drug interactions, adverse drug reactions, adherence, medicine burden, treatment burden, stigma, social support, and patient-healthcare provider relationships. Nine interventions were identified to target older persons, five aimed at improving medication adherence, two to reduce drug interactions, and two for medicine self-management initiatives. Further in-depth research is needed to understand older PLWH's experiences of medicines and their priority issues. Adherence-focused interventions are predominant, but there is a scarcity of interventions aimed at improving medicine experiences for this population. Multi-faceted interventions are needed to achieve medicine optimisation outcomes for PLWH. This study is registered with PROSPERO registration number: CRD42020188448.