BACKGROUND: Trans-women sex workers bear the greatest brunt of HIV and other sexually transmitted infections (STI). Trans-women are 49 times more at risk of HIV infections compared to the general population. However, they remain underserved and continue to grapple with access to and utilisation of HIV/STI prevention services. This study explored barriers to access and utilisation of HIV/STI prevention services and associated coping mechanisms. METHODS: This exploratory qualitative study was conducted among trans-women sex workers in the Greater Kampala Metropolitan area, Uganda. A total of 22 in-depth interviews, 6 key informant interviews and 9 focus group discussions were conducted to obtain data on barriers to access and utilisation of HIV and other STI prevention and care services, and coping strategies of trans-women sex workers. Data were analysed through thematic analysis using a hybrid of inductive and deductive approaches. RESULTS: Individual level barriers to access and utilisation of HIV/STI prevention and care services included internalised stigma and low socio-economic status. Healthcare system barriers included social exclusion and lack of recognition by other key population groups; stigmatisation by some healthcare providers; breach of confidentiality by some healthcare providers; limited hours of operation of some key population-friendly healthcare facilities; discrimination by straight patients and healthcare providers; stockout of STI drugs; inadequate access to well-equipped treatment centres and high cost of drugs. At community level, transphobia hindered access and utilisation of HIV/STI prevention and care services. The coping strategies included use of substitutes such as lotions, avocado or yoghurt to cope with a lack of lubricants. Herbs were used as substitutes for STI drugs, while psychoactive substances were used to cope with stigma and discrimination, and changing the dress code to hide their preferred gender identity. CONCLUSIONS: Individual, community and healthcare system barriers hindered access and utilisation of HIV/STI prevention and care services among the trans-women sex workers. There is a need to create an enabling environment in order to enhance access to and utilisation of HIV/STI prevention and care services for trans-women sex workers through sensitisation of healthcare providers, other key population groups and the community at large on the transgender identity.