This study examined the risk factors for active syphilis infection in a subset of nationally-representative population-based survey of Zambian men and women. Syphilis prevalence was 6.5% for women = 2107) and 7.4% for men (N = 1745). In the multivariate model, province was a strong risk factor for active syphilis infection, with Copperbelt, Eastern, Luapula, Lusaka, North-Western and Western Provinces presenting significantly higher risk for women, and Copperbelt, Eastern and Lusaka Provinces presenting significantly higher risk for men compared to the Northern Province. In addition to province, age, education, age at first intercourse, marital status, history of genital sore or discharge, and having ever paid for sex were independent predictors of syphilis infection. Given the ongoing HIV-1 epidemic in Zambia, more aggressive diagnosis and treatment of active syphilis infections, particularly in high-risk provinces, are important strategies to reduce reproductive morbidity and curb HIV-1 transmission.