Sexually transmitted infections (STIs) have been identified as cofactors of HIV transmission. Greater understanding of local STI burdens can assist in the development of more effective STI and HIV prevention strategies. The aim of this study is to determine the prevalence and incidence of STIs among South Indian men and women identified to be at increased risk for HIV infection. Individuals at increased risk for HIV infection were enrolled in a prospective longitudinal study in Chennai, India (n = 480) between August 2002 and December 2003. Participants were enrolled from patients seeking services at an sexually transmitted disease (STD) clinic and a confidential HIV testing and counseling program. The most common prevalent STIs were herpes simplex virus (HSV)-2 (50% of women, 29% of men), syphilis (11% of women, 8% of men), and Trichomonas vaginalis (6% of women). At enrollment, women, participants with no schooling, participants with greater than four sex partners, and single participants were found to be at increased risk for HSV-2 infection (p < 0.05). The two most common incident STIs at 12 months were HSV-2 with 12% of men and 8% of women testing positive and hepatitis B with 2% of men and 5% of women testing hepatitis B surface antigen (HBsAg) positive. In this cohort of South Indian men and women with a high background prevalence of HSV-2, suppressive therapy against herpes replication may have a substantial impact in reducing both HSV-2 transmission and HIV acquisition. With the high incidence of STIs, targeted prevention and clinical management strategies among individuals practicing high risk behaviors may help to slow the continued spread of HIV in India.