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Shortages of essential medicines are a daily occurrence in many of South Africa (SA)’s public health facilities. This study focuses on the responses of healthcare workers to stock-outs, investigating how actors at the ‘front line’ of public health delivery understand, experience and respond to shortages of essential medicines and equipment in their facilities. Findings are based on focus groups, observations and interviews with healthcare workers and patients at healthcare facilities in the Eastern Cape Province of SA, conducted as part of the Mzantsi Wakho study. The research revealed a discrepancy between ‘informal’ definitions of stock-outs and their reporting through formal stockout management channels. Front-line healthcare workers had designed their own systems for classifying the severity of stock-outs, based on the product in question, and on their potential to access stocks from other facilities. Beyond formal systems of procurement and supply, healthcare workers had established vast networks of alternative communication and action, often using personal resources to procure medical supplies. Stock-outs were only reported when informal methods of stock-sharing did not secure top-up supplies. These findings have implications for understanding the frequency and severity of stock-outs, and for taking action to prevent and manage stock-outs effectively.