Background: We compared the herpes simplex virus type 2 (HSV-2) seroprevalence in a contemporary HIV cohort with the general US population and determined risk factors for HSV-2 infection among HIV-infected persons. Methods: The Study to Understand the Natural History of HIV and AIDS in the Era of Effective Therapy (SUN) Study is a prospective observational cohort of 700 HIV-infected adults enrolled in 4 US cities between 2004 and 2006. At baseline, participants completed a behavioral risk questionnaire and provided specimens for HSV-2 serology. We calculated HSV-2 seroprevalence, standardized by age, gender, and race among HIV-infected persons compared with the general US adult population, using data from the National Health and Nutrition Examination Survey from 2003 to 2006. We examined risk factors associated with HSV-2 infection among HIV-infected persons using multivariate logistic regression. Results: Among 660 (94%) SUN participants with adequate specimens for HSV-2 serologic testing, 548 (83%) were 20 to 49 years old (median age, 39 years; 77% male; 59% non-Hispanic white; median CD4 count, 470 cells/mm; 74% with HIV RNA viral loads <400 copies/mL). HSV-2 seroprevalence was significantly higher among HIV-infected adults (59.7%, 95% confidence interval: 55.8-63.6) compared with the general US population (19.2%, 95% confidence interval: 17.5-21.1). In multivariate analysis, we found that older age, female gender, black non-Hispanic race/ethnicity, being currently unemployed, high-risk anal HPV infection, and longer duration since HIV diagnosis were associated with significantly higher odds of HSV-2 infection. Conclusion: HSV-2 seroprevalence is 3 times as high among HIV-infected adults as in the general US population. Clinicians should be aware that increased risk for HSV-2 infection was distributed broadly among HIV-infected persons and not limited to those with high-risk sexual behaviors. © 2012 American Sexually Transmitted Diseases Association All rights reserved.