BACKGROUND: In Cambodia, HIV infection remains high among female entertainment and sex workers (FESW) and the use of amphetamine-type stimulants (ATS) is an independent risk factor for unprotected sex and sexually transmitted infections among this group. For decades public health approaches to HIV prevention in low and middle income countries (LMIC) have attempted to target the macro-power relations that shape risk behaviour with structural interventions. Recent research has highlighted that interventions that combine ATS risk reduction, in the form of financial incentives for abstinence, with existing HIV prevention programmes, may also play an important role. However, whether this approach goes far enough as a response to structural drivers of risk requires further examination. METHODS: Semi-structured in-depth interviews were conducted with 30 FESW (mean age 25 years) from five provinces in Cambodia, as part of formative research for the implementation of the Cambodia Integrated HIV and Drug Prevention (CIPI) trial. The aim was to explore the contexts and drivers of ATS use. Data were analysed using grounded theory. RESULTS: In addition to increasing occupational functionality, ATS were used to control pervasive feelings of ‘sadness’ in relation to the lived experience of poverty, family and relationship problems. Feeling sad could be viewed as an expression of social suffering, in response to competing priorities and seemingly inescapable constraints imposed by a lack of options for income generation, gender inequalities and stigma. Participants expressed interest in microenterprise (ME) opportunities, particularly vocational training, that could create new work opportunities beyond sex work and ATS use. CONCLUSION: In addition to reducing ATS use, HIV prevention interventions need to target sources of sadness and social suffering as drivers of risk among FESW in this context. The inclusion of ME opportunities in HIV prevention, to alleviate social suffering, warrants further investigation through qualitative and ethnographic research.