We explore the potential benefits of integrating preexposure prophylaxis (PrEP) into combination HIV prevention for female sex workers (FSWs) and the likely challenges to implementation. Evidence for the biological effectiveness of PrEP in women who can adhere to daily dosing is strong. FSWs in many countries bear the brunt of the HIV epidemic. Current combination prevention approaches enable many FSWs to remain HIV-free, but in some settings FSWs are unable to mitigate their risk. PrEP provides a new prevention tool for these women. To benefit, HIV-negative FSWs need to perceive that they are at risk, be motivated and able to take PrEP daily and to attend health services for prescription refill and clinical monitoring. FSWs face particular structural challenges to PrEP uptake and use, including stigmatizing health services; fear of disclosure to other FSWs and clients; fear of the authorities; lack of social support; substance use; unplanned travel and risk compensation many of which can be addressed through combination prevention approaches. For those FSWs who are unable to mitigate their HIV risk, PrEP, if adequately supported and integrated with combination prevention, may empower them to remain HIV-free.