Objective: This study investigated the efficacy of the prophylactic human papillomavirus (HPV) vaccine started at 2009- 2013 in Japan. Materials and Methods: The study involved 1529 eligible women aged 16 to 39 years who visited 11 outpatient clinics for various reasons in Japan. All these patients underwent an examination of HPV genotype and a Pap test using cervical cell samples. Two hundred ninty-nine women (19.6%) received the prophylactic HPV vaccine (bivalent :quadrivalent vaccine ratio = 2:1). Of the 5062 participants in the Japanese Human Papillomavirus Disease Education and Research Survey (J-HERS 2011), which was conducted in the pre-vaccination era, 3236 eligible participants were included as controls. Results: In the present study (J-HERS 2021), highest rate for HPV vaccination (53%) was observed in 22- to 27-year-old patients. Vaccinated ones showed 49% protection against low-grade intraepithelial lesions (LSIL) and atypical squamous cells not excluding high-grade squamous intraepithelial lesions (ASCH) or worse (LSIL/ASCH+), and 100% protection against high-grade squamous intraepithelial lesions (HSIL) or worse (HSIL+). The prevalences of HPV16 and HPV18 infections also significantly decreased (HPV16; 95% and HPV18; 100%), but there were no differences in HPV6 and HPV11 infections by the vaccination. The prevalences of HPV51 and HPV59 increased with vaccination, although these changes were not confirmed in the comparative study with J-HERS 2011. Comparisons between the pre-vaccination period (J-HERS 2011) and post-vaccination period (J-HERS 2021) revealed reduction rates of 43%, 51%, 88%, and 62% were observed for HPV16, HPV18, HPV16/18, and HPV31/58 infections, respectively. Similarly, reduction rates of 62% and 71% for LSIL/ASCH+ and HSIL+, respectively. The reduction rate for LSIL/ASCH+ was 88% in 16- to 21-year-old patients, whereas the rate for HSIL+ was 87% in 28- to 33-year-old patients. C onclusion: Bivalent or quadrivalent vaccines provided 100% protection against high-grade squamous cell lesions (suggestive of CIN2 or CIN3) in young women aged < 39 years at 9 to 12 years after initiation of the first nationwide HPV vaccination program in Japan. Cross-protection against HPV31 and HPV58 is likely to occur, although some HPV type replacements are inconsistent across vaccination regimens. This demonstrates a high effectiveness of HPV vaccine. In contrast, we worry about no reduction of cervical cancer in younger generation (born in 1997-2007) who are rarely vaccinated due to long term suspension of this vaccine recommendation in Japan.