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Climate change is directly and indirectly linked to human health, including through access to treatment and care. Our systematic review presents a systems understanding of the nexus between drought and antiretroviral treatment (ART) adherence in HIV-positive individuals in the African setting. Narrative synthesis of 111 studies retrieved from Web of Science, PubMed/Medline, and PsycINFO suggests that economic and livelihoods conditions, comorbidities and ART regimens, human mobility, and psycho-behavioural dispositions and support systems interact in complex ways in the drought-ART adherence nexus in Africa. Economic and livelihood-related challenges appear to impose the strongest impact on human interactions, actions and systems that culminate in non-adherence. Indeed, the complex pathways identified by our systems approach emphasise the need for more integrated research approaches to understanding this phenomenon and develop interventions.