INTRODUCTION:Female and male sex workers experience heightened vulnerability to HIV and other health harms that are compounded by substance use, physical and sexual violence, and limited access to health services. In Kisumu, Kenya, where sex work is widespread and substance use is a growing public health concern, offering pre-exposure prophylaxis (PrEP) for HIV prevention could help curtail the HIV epidemic. Our study examines "syndemics," or mutually reinforcing epidemics of substance use, violence and HIV, in relation to PrEP acceptability and feasibility among female and male sex workers in Kenya, one of the first African countries to approve PrEP for HIV prevention. METHODS:From 2016 to 2017, sex workers in Kisumu reporting recent alcohol or drug use and experiences of violence participated in qualitative interviews on HIV risk and perspectives on health service needs, including PrEP programming. Content analysis identified themes relating to PrEP knowledge, acceptability, access challenges and delivery preferences. RESULTS:Among 45 female and 28 male sex workers, median age was 28 and 25 respectively. All participants reported past-month alcohol use and 91% of women and 82% of men reported past-month drug use. Violence was pervasive, with most women and men reporting past-year physical (96% women, 86% men) and sexual (93% women, 79% men) violence. Concerning PrEP, interviews revealed: (1) low PrEP knowledge, especially among women; (2) high PrEP acceptability and perceived need, particularly within syndemic contexts of substance use and violence; and (3) preferences for accessible, non-stigmatizing PrEP delivery initiatives designed with input from sex workers. CONCLUSIONS:Through a syndemic lens, substance use and violence interact to increase HIV vulnerability and perceived need for PrEP among female and male sex workers in Kisumu. Although interest in PrEP was high, most sex workers in our sample, particularly women, were not benefiting from it. Syndemic substance use and violence experienced by sex workers posed important barriers to PrEP access for sex workers. Increasing PrEP access for sex workers will require addressing substance use and violence through integrated programming.