A simplified dose regimen of the live, attenuated, tetravalent dengue vaccine (CYD-TDV) could have the potential to facilitate easier implementation of immunization programs against symptomatic virologically-confirmed dengue (VCD) in dengue seropositive individuals aged ≥ 9 years. This post-hoc analysis of two Phase III studies (CYD14 [NCT01373281] and CYD15 [NCT01374516]) in dengue endemic areas assessed the efficacy of CYD-TDV by dengue serostatus between dose 1 and 2 (at Month [M] 6), between dose 2 and 3 (at M12), and from dose 3 to M25. Baseline dengue serostatus (seropositive or seronegative) was determined based on measured dengue neutralizing antibody titers with the 50% plaque reduction neutralization test (PRNT₅₀) or ascertained by logistic regression-based multiple imputation (MI) to predict PRNT₅₀. Vaccine efficacy against symptomatic VCD was assessed by age and baseline dengue serostatus using a case-cohort framework. Dengue neutralizing antibody geometric mean titers (GMTs) were measured with the PRNT₅₀ at 28 days post-dose 2 and 3. Vaccine efficacy estimates in seropositive participants aged ≥ 9 years at post-dose 1, 2, and 3 were 80.5% (95% CI, 66.2, 88.7), 82.0% (95% CI, 70.5, 89.0), and 75.2% (95% CI, 65.9, 81.9), respectively. In seropositive participants aged < 9 years, vaccine efficacy estimates were 48.5% (95% CI, –24.3, 78.6), 68.3% (95% CI, 34.5, 84.7), and 65.3% (95% CI, 40.2, 79.9), respectively. CYD-TDV efficacy was null to modest after any dose in seronegative participants, regardless of age group. Seropositive participants aged ≥ 9 years in the CYD-TDV group had GMTs post-dose 3 that did not exceed those observed post-dose 2. In conclusion, CYD-TDV has high efficacy against VCD from the first dose through to M25, with estimates at post-dose 1 and 2 similar to or higher than those at post-dose 3 in seropositive participants aged ≥ 9 years, consistent with immunogenicity data.