The Jamaican government has provided targeted HIV and sexually transmitted infection prevention, treatment, and other services for female sex workers (FSW) since 1989. HIV prevalence among FSW declined from 20 to 12 % between 1989 and 1994, then to 9 % in 2005, 5 % in 2008, and 4.1 % in 2011. This article distills the literature and two decades of experience working with FSW in Jamaica. Drawing on the constant comparative method, we put forward an innovative conceptual framework for explaining sexual decision-making and risk behaviors within both transactional and relational sexual situations. This framework helps fill the gaps in existing models that focus on individual behaviors. The model identifies interactions between environmental and structural elements of sex work, and three individual-level factors: risk perception, perceived relationship intimacy, and perceived control, as the four primary mediating factors influencing sexual decision-making among FSW. We propose that other factors such as violence, socioeconomic vulnerability, and policy/legal frameworks influence sexual decision-making through these primary mediating factors. This conceptual model may offer a useful framework for planning and evaluating prevention interventions among sex workers. However, it remains to be tested in order to establish its value.