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In the era of effective prevention of mother-to-child transmission of HIV, the same psychosocioeconomic factors that predispose to mother-to-child transmission also substantially increase the likelihood of antiretroviral therapy failure in infected infants. For HIV-infected infants to benefit from early infant diagnosis and treatment initiation, into which much funding and effort is now invested, it is vital that these unmet needs of high-risk mothers are urgently attended to. From an ongoing study of early infant diagnosis and treatment following in utero transmission in KwaZulu-Natal, South Africa, we describe four cases to highlight these challenges facing transmitting mothers that contribute to treatment failure in their infants.