Home to one fifth of all people living with HIV, South Africa carries the world’s heaviest burden of this disease. While a significant proportion of those infected are immigrants from other African high-prevalence countries, little is known about how these migrants engage with healthcare systems in shifting cultural and clinical settings. This article draws on fieldwork from migrant communities and twenty-one ethnographic life histories told by HIV-positive Mozambicans in a major South African HIV clinic. From their collective narratives, a range of structural vulnerabilities are found that limit immigrants’ access to, and proper integration within, healthcare services. These include perilous migration, xenophobia and deportation, exclusion and exploitation, language barriers, medical pluralism, cultural estrangement, social isolation, and the stigmas of being HIV-positive. In conjunction, these structural factors may delay treatment-seeking and inhibit drug adherence, which could increase rates of morbidity and mortality as well as contribute to viral mutation and antiretroviral drug resistance.