Although highly effective vaccines have been available for almost 70 years, an estimated 200,000 cases of YF, including 30,000 deaths, still occur annually. This study evaluated the safety of two yellow fever (YF) vaccines [Stamaril and Vacina Contra Febre Amarela (VCFA)]. A total of 2,514 subjects were randomized equally to receive Stamaril or VCFA. Immediate reactions occurring within 30 minutes after vaccination, and solicited local and systemic reactions occurring within eight days, were monitored. Unsolicited local, systemic adverse events and serious adverse events (SAE) were recorded for 21 days after vaccination. Solicited local and systemic adverse reactions were reported by 15.3-17.6% and 30.4-31.6% of the Stamaril and VCFA groups, respectively. Only 56 of the 2,514 study subjects (2.2%) reported a severe solicited adverse reaction, 25 in the Stamaril group (1.99%) and 31 in the VFCA group (2.49%), (p=0.403). Ten subjects (0.8%) in each group reported at least one severe solicited local reaction (p = 0.988). A total of 18 Stamaril subjects (1.43%) and 21 VCFA subjects (1.68%) reported at least one severe solicited systemic reaction (p = 0.617) One SAE considered related to vaccination occurred, polymyalgia in the VCFA group. No immediate reactions to vaccination were seen. Vaccine-related unsolicited events were infrequent, 1.4% in the Stamaril group and 2.0% VCFA group, generally of mild or moderate intensity. We conclude that the safety profiles of Stamaril and VCFA support routine vaccination to prevent YF in residents of and travelers to endemic areas of South America and Africa.