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Globally, COVID-19 has impacted lives and livelihoods. Women living with HIV and/or at high risk of acquiring HIV are socially and economically vulnerable. Less is known of the impact of COVID-19 public health responses on women from key and vulnerable populations. The purpose of this cross-sectional survey conducted in four South African provinces with a high burden of HIV and COVID-19 from September to November 2021 was to advance understanding of the socio-economic and health care access impact of COVID-19 on women living with HIV or at high risk of acquiring HIV. A total of 2 812 women >15 years old completed the survey. Approximately 31% reported a decrease in income since the start of the pandemic, and 43% an increase in food insecurity. Among those accessing health services, 37% and 36% reported that COVID-19 had impacted their access to HIV and family planning services respectively. Economic and service disruptions were enhanced by living in informal housing, urbanisation and being in the Western Cape. Food insecurity was increased by being a migrant, having fewer people contributing to the household, having children and experience of gender-based violence. Family planning service disruptions were greater for sex workers and having fewer people contributing to the household. These differentiated impacts on income, food security, access to HIV and family planning services were mediated by age, housing, social cohesion, employment and household income, highlighting the need for improved structural and systemic interventions to reduce the vulnerability of women living with HIV or at high risk of acquiring HIV.