Background <p>Access to health protection and preventive services remains a challenge within the formal healthcare sector owing to patient demands and repeated admissions that are costly to the government. The Centers for Diseases Control and Prevention acknowledges that informal markets are important centres of commerce for many people and a source of necessary goods. However, markets are also confirmed to be a major risk for the transmission of droplet infections. The purpose of the study was to understand the knowledge and behaviour of minibus taxi drivers, street food and/or fruit vendors who are part of informal markets in the Eastern Cape, South Africa, toward hand hygiene practice in view of cross-infection and control thereof.</p> Design and methods <p>This descriptive and explorative qualitative study utilised a convenience, purposive and criterion-based sampling method. Thematic data analysis of the recorded individual interviews was conducted from 19 taxi drivers and 21 vendors. An independent coder assisted to finalise the results. Three main themes and six sub-themes were derived from the data analysis and recommendations for clinical practice and future research made.</p> Results <p>Taxi drivers and vendors experienced guilt, fear, and anxiety about infection, death, and transmitting COVID-19 infection to their families. Participants showed poor understanding of droplet infection, hand hygiene, and transmission routes of droplet infection while having misconceptions such as the role of wind and uncertainty about prevention measures about COVID-19 which was the current disease involving the need for hand hygiene. Participants reported insufficient support in terms of finance and health education from business owners and government respectively.</p> Conclusion <p>The study found that taxi drivers and vendors experienced limited knowledge of droplet infection and role of hand hygiene in such circumstances. This limitation aggravated their fear, anxiety during the COVID-19 pandemic. The attitude was that of taking the risk and continue with their jobs while hoping for some educational and financial support from government and taxi owners in future. Participants had partial knowledge of hand hygiene but demonstrated limited understanding of droplet infection. Lack of droplet infection and hand hygiene knowledge stemmed from not ever being informed about such diseases and thus recommended for assistance in this regard. It is thus concluded that public health nurses and officials have still much work to do, as basic hand hygiene principles are yet to be communicated with success to some of our communities.</p>