Importance Human papillomavirus (HPV) vaccine clinical trials demonstrate high vaccine efficacy, but postlicensure population-level effectiveness data are needed to inform vaccination and cancer-prevention recommendations and policies. Little is known about effectiveness in adolescent girls and young adult women at high risk for HPV-related cancers or after 9-valent HPV vaccine (9vHPV) introduction. Objective To examine effectiveness and herd protection over the first 17 years after HPV vaccine introduction in adolescent girls and young women at increased risk for HPV infection and related cancers. Design, Setting, and Participants This cross-sectional study analyzed data from 6 surveillance studies from 2006 to 2023. A consecutive sample of sexually experienced adolescent girls and young women aged 13 to 26 years was recruited from clinical settings. Exposure Participants were stratified by HPV vaccination status; those who received at least 1 vaccine dose were defined as vaccinated. Main Outcomes and Measures Effectiveness and herd protection were assessed by comparing proportions of vaccinated and unvaccinated participants positive for at least 1 type in the 2-valent vaccine (2vHPV), 4-valent vaccine (4vHPV), and 9vHPV in each of 6 studies. The prevalence of vaccine-type HPV was compared in vaccinated participants from surveillance studies 2 through 6 vs participants recruited in surveillance study 1, all of whom were unvaccinated. Inverse probability of treatment weighting with propensity score was used to balance between-wave differences in participant characteristics. Results Of 2335 participants (mean [SD] age, 18.9 [2.7] years; 1526 African American [65.4%], 13 Asian [0.6%], 6 Native American [0.3%], 582 White [24.9%], and 151 multiracial [6.5%]; 173 Hispanic [7.4%]), 1195 participants (51.2%) reported a sexually transmitted infection history and 1843 participants (78.9%) reported 2 or more male sex partners. Vaccination rates increased from 0 of 371 participants to 330 of 402 participants (82.1%) from 2006 to 2023. Among vaccinated participants, positivity decreased from 93 of 371 participants (27.7%) to 1 of 330 participants (0.4%) for 2vHPV (relative difference, 98.4%), 118 participants (35.4%) to 3 participants (2.1%) for 4vHPV (relative difference, 94.2%), and 163 participants (48.6%) to 21 participants (11.8%) for 9vHPV (relative difference, 75.7%). Among unvaccinated participants, positivity decreased from 93 of 371 participants (25.8%) to 3 of 72 participants (7.3%) for 2vHPV (relative difference, 71.6%), 118 participants (25.3%) to 4 participants (6.1%) for 4vHPV (relative difference, 75.8%), and 163 participants (42.7%) to 13 participants (31.1%) for 9vHPV (relative difference, 27.2%). For positivity rates, counts are raw numbers and percentages are propensity score adjusted. Adjusted logistic regression demonstrated significant reductions in the odds of at least 1 HPV type in the 2vHPV and 4vHPV among all (adjusted odds ratio [aOR], 0.03; 95% CI, 0.01 to 0.07 and aOR, 0.06; 95% CI, 0.03 to 0.10, respectively), vaccinated (aOR, 0.01; 95% CI, &lt;0.01 to 0.05 and aOR, 0.04; 95% CI, 0.02 to 0.08, respectively), and unvaccinated (aOR, 0.23; 95% CI, 0.08 to 0.63 and aOR, 0.19; 95% CI, 0.07 to 0.52, respectively) participants and in the 9vHPV among all (aOR, 0.22; 95% CI 0.16 to 0.31) and vaccinated (aOR, 0.14; 95% CI 0.09 to 0.21) participants. Conclusions and Relevance In this study, population-level effectiveness and herd protection were robust 17 years after HPV vaccine introduction, even in sexually experienced adolescent girls and young women at relatively high risk for HPV who may not have received the full vaccination series.