Background: Nearly 3% of Americans experience severe and persistent mental illness (SPMI) and behaviors that place affected individuals at risk for sexually transmitted infections (STIs) are common. Few data describe the prevalence of risk behaviors or STI among persons with SPMI. We aim to quantitate STI/human immunodeficiency virus risk and determine the STI prevalence amongst outpatient psychiatric clinic attendees. Methods: Psychiatric outpatients were approached to participate in an interviewer-administered survey collecting data on their sexual history, psychiatric history, and risk behaviors. Females submitted self-collected vaginal swabs, whereas males submitted urine to be tested for Neisseria gonorrhoeae, Chlamydia trachomatis, and Trichomonas vaginalis (women only). Results: The prevalence of N. gonorrhoeae was 1%, C. trachomatis 3.3% and T. vaginalis 15.7%. Exchanging sex for drugs was the only behavior independently associated with having an STI in this population. Conclusions: Taking a sexual history in persons with SPMI is important. Those engaging in high-risk behavior should be routinely screened for STI/human immunodeficiency virus allowing for detection, treatment, and preventive education. Copyright © 2008, American Sexually Transmitted Diseases Association. All rights reserved.