The World Health Organization estimates that at least 12 million people are infected with syphilis in the world. Southeast Asia accounts for 5.8 million; Africa accounts for 3.5 million. There has been controversy in using the two kinds of antibiotics for early syphilis. A systematic review comparing these antibiotics could affect treatment guidelines. The aim of this study was to evaluate the efficacy and safety of azithromycin vs. penicillin G benzathine for early syphilis and a meta-analysis to compare these two kinds of antibiotics for early syphilis. Four randomized controlled trials met the inclusion criteria; 476 patients were evaluated for their cure rate. Cure rates were 95.0% (227/239) for azithromycin and 84.0% (199/237) for penicillin G benzathine. After pooling the data, the difference in efficacy was computed. Cure rate (OR=1.37), 95% CI (1.05, 1.77) and the risk difference for cure rate between the two drugs were statistically significant. Although the gastrointestinal adverse effect of azithromycin is five times more than the adverse effect of penicillin G benzathine, the differences are not significant. Azithromycin achieved a higher cure rate than penicillin G benzathine in a long follow-up.