© 2017 The Southern Medical Association. Objectives: Increased sexual partner numbers may contribute to sexually transmitted infection (STI) risk for some but not all women. This study compared women reporting having four or more partners during the preceding year (multiple partnership group) with those reporting having one partner (single partnership group) with regard to sexually risky behaviors and other modifiable predictors of STI risk. We also compared the prevalence of bacterial vaginosis, trichomoniasis, chlamydia, gonorrhea, syphilis, herpes simplex virus type 2, and human immunodeficiency virus among groups. Methods: Eligible female patients 16 years and older presenting to an urban STI clinic completed a questionnaire followed by a pelvic examination with testing for bacterial vaginosis, trichomoniasis, chlamydia, and gonorrhea. Serum was collected for human immunodeficiency virus, syphilis, and herpes simplex virus type 2 serological testing. Results: Between May 2011 and October 2013, 213 participants were enrolled in the study: 107 in the multiple partnership group and 106 in the single partnership group. Women with multiple partners were more likely to be younger, prefer to have sex with men and women, report drug use, engage in sex for money/drugs, have sex with homosexual/bisexual men, have sex with a partner who has been incarcerated, have sex while drinking alcohol, and have a new partner as the most recent partner. Women in the single partnership group were more likely to report a regular partner and no condom use at their last sexual encounter. STI prevalence rates were high in both groups and not significantly different except for Chlamydia trachomatis, which was more common in women with multiple sex partners (18% vs 6%, P = 0.01). In logistic regression analysis adjusted for age, education, partner number group, and condom use at last sexual encounter, only age 25 years and younger was associated with chlamydia (odds ratio 7.82, confidence interval 2.23-27.46). Conclusions: The lack of condom use with regular sex partners in the single partnership group may have mitigated the risks associated with participation in sexually risky behaviors among the multiple partnership group, resulting in high STI rates among both groups. Women should be counseled regarding the risk of STI transmission from their regular partner or partners in addition to a casual partner or partners.