Objectives: Clients of female sex workers (FSWs) are an important target group for human immunodeficiency virus/sexually transmitted infection (HIV/STI) prevention. This study aimed to estimate their HIV and other STI prevalence, examine their risk behaviors, and evaluate their role as a bridge population in the spread of HIV/STIs. Methods: A cross-sectional study was performed among 553 clients recruited in commercial sex sites in the province of Escuintla, Guatemala. They were interviewed and tested for HIV and other STIs. Results: Half of the clients who were approached refused participation. Median age was 28.9 years; 57.7% had a regular partner, of whom, 10.1% had concurrent noncommercial partnerships. Consistent condom use with FSWs and regular partners was 72.5% and 17.1%, respectively. Approximately 18% formed a bridge, and 40.0% a potential bridge. Among those who provided samples (70.5% provided a blood sample and 89.7%, urine sample), prevalence of HIV, syphilis, gonorrhea, chlamydia, and herpes simplex virus 2 was 1.5%, 1.0%, 0.8%, 5.5%, and 3.4%, respectively. Unprotected sex with FSWs and drug use just before sex were risk factors for having any STI (9.8% of participants). Bridge clients were significantly less educated, more employed, paid lower prices to the FSW just visited, and had a previous STI. Conclusions: There is a relatively high prevalence of HIV in clients compared to national estimates, and a substantial proportion of them act as a bridge for HIV/STI transmission between FSWs and the general population in Escuintla. Given that this is fuelling the current HIV epidemic, preventive interventions addressing this hard-to-reach group are urgently required. © 2011 American Sexually Transmitted Diseases.