Background: Several studies have shown the efficacy of the Human Papillomavirus (HPV) vaccine in reducing the risk of cervical cancer. Given the recent introduction of the HPV vaccine, there has been limited evidence linking vaccination to a decreased likelihood of developing other HPV-related cancers. Methods: A retrospective cohort study was conducted using a patient population selected from the TriNetX United States Collaborative Network. Patients 9-39 years old attending medical encounters where any vaccine was administered between 1/1/2010 and 12/31/2023 were divided into two cohorts: patients vaccinated for HPV at least five years prior and those no history of HPV vaccination. Outcomes were malignancies at the following sites: Head and Neck (HNC), Cervix, Anus & Anal Canal, Penis, Vulva, and Vagina. Patients with no prior history of cervical dysplasia undergoing Pap smear were observed for atypical cytology. Propensity score matching was performed to match cohorts for age, race/ethnicity, tobacco use, and BMI. Results: Males vaccinated for HPV (n = 760,540) were at decreased odds for HPV-related cancers (odds ratio (OR) = 0.46, 95 % confidence interval (CI) = 0.29-0.72, p-value = 0.001). This finding was primarily driven by a significant reduction in HNC (OR = 0.44, CI = 0.26-0.73, p = 0.0016). Females vaccinated for HPV (n = 945,999) had lower odds for cervical (OR = 0.71, CI = 0.52-0.96, p-value = 0.027) cancers and HPV-related cancers overall (OR = 0.73, CI = 0.57-0.94, p = 0.013). Odds of HNC (OR = 0.67, CI = 0.42-1.1, p = 0.10) and Vulvar/Vaginal cancer (OR = 1.67, CI = 0.81-3.41, p = 0.16) were not significantly different in vaccinated females compared to controls. Vaccinated females were less likely to develop High Grade Squamous Intraepithelial Lesions (HGSIL), (OR = 0.44, CI = 0.30-0.65, p < 0.0001), and Carcinoma In-Situ(OR = 0.422, CI = 0.25-0.72, p = 0.002). Conclusions: These results suggest early evidence of efficacy in the vaccine in preventing the development of several types of malignancies and pre-malignant dysplasia caused by HPV.