This mixed-methods study examined the acceptability of a hypothetical couples-based HIV prevention program for female sex workers and their intimate (non-commercial) male partners in Mexico. Among 320 participants, 67 % preferred couples-based over individual programs, particularly among men. Reasons cited for preferring couples-based programs included convenience and health benefits for both partners. Participants reported that they would benefit from general health information and services, HIV counseling and testing, job training (particularly for men) and other services. However, qualitative interviews revealed that barriers relating to the environment (i.e., poor access to services), providers (i.e., lack of a therapeutic alliance), and intimate relationships (i.e., mistrust or instability) would need to be addressed before such a program could be successfully implemented. Despite women’s concerns about privacy and men’s preferences for gender-specific services, couples-based HIV prevention programs were largely acceptable to female sex workers and their intimate male partners.