Aim The quadrivalent human papillomavirus (4vHPV) vaccine has demonstrated efficacy and immunogenicity and was generally well tolerated in clinical trials conducted in Japan. We report a detailed safety analysis of injection-site reactions in female Japanese 4vHPV clinical trial participants. Methods This post-hoc analysis included data from 2 double-blind, placebo-controlled phase II clinical trials of a 3-dose (Day 1, Month 2, Month 6) regimen of 4vHPV vaccine in Japanese young women aged 18–26 years (N = 1021; NCT00378560) and girls aged 9–17 years (N = 107; NCT00411749). Injection-site and systemic adverse events (AEs) were monitored using vaccination report cards for 15 days after each vaccine dose; serious AEs were reported throughout the trials. Post-hoc analyses of data from these trials were performed to examine details of injection-site AEs, including day of onset, time from onset to resolution, and maximum intensity. Results Injection-site AEs were reported by 85.6% of 4vHPV vaccine recipients and 72.4% of placebo recipients, most commonly erythema, pain, pruritus, and swelling (each >5% of 4vHPV vaccine recipients). The majority of injection-site AEs had an onset within 3 days of vaccination and were mild to moderate in intensity; few 4vHPV vaccine recipients reported severe injection-site AEs (2.0% overall). All injection-site AEs resolved, and most (4vHPV: 87.5%; placebo: 92.7%) resolved within 5 days of onset. Conclusions Most injection-site reactions are mild or moderate in intensity and of short duration. The 3-dose regimen of 4vHPV vaccine is well tolerated in Japanese female clinical trial participants based on this post-hoc analysis. These results will further support safety communication between healthcare providers and vaccine recipients regarding the HPV vaccine. Trial registration Clinicaltrials. gov: NCT00378560 and NCT00411749.