Immunogenicity and safety of a recombinant, live-attenuated, tetravalent dengue disease vaccine (CYD-TDV) was evaluated in children/adolescents in Brazil. In this observer-blind, placebo-controlled, phase II single-center study, children/adolescents (ages 9-16 years) were randomized to receive CYD-TDV or placebo at 0, 6, and 12 months. Immunogenicity was assessed using a 50% plaque neutralization test. Overall, 150 participants were enrolled (CYD-TDV: N = 100; placebo: N = 50). Injection site pain and headache were the most common solicited injection site and systemic reactions. Unsolicited adverse events (AEs) and serious AEs were similar between groups. No serious AEs were vaccine-related. Geometric mean titers against all dengue virus serotypes increased with CYD-TDV vaccination and were 267, 544, 741, and 432 1/dil for serotypes 1-4, respectively, after dose 3, representing a mean fold increase from baseline of 5, 6, 6, and 20, respectively. CYD-TDV vaccination elicited a neutralizing antibody response against serotypes 1-4 and was well-tolerated in children/adolescents in a dengue-endemic region.