Prophylactic human papillomavirus (HPV) vaccination programs constitute major public health initiatives worldwide. We assessed the global effect of quadrivalent HPV (4vHPV) vaccination on HPV infection and disease. PubMed and Embase were systematically searched for peer-reviewed articles from January 2007 through February 2016 to identify observational studies reporting the impact or effectiveness of 4vHPV vaccination on infection, anogenital warts, and cervical cancer or precancerous lesions. Over the last decade, the impact of HPV vaccination in real-world settings has become increasingly evident, especially among girls vaccinated before HPV exposure in countries with high vaccine uptake. Maximal reductions of approximately 90% for HPV 6/11/16/18 infection, approximately 90% for genital warts, approximately 45% for low-grade cytological cervical abnormalities, and approximately 85% for high-grade histologically proven cervical abnormalities have been reported. The full public health potential of HPV vaccination is not yet realized. HPV-related disease remains a significant source of morbidity and mortality in developing and developed nations, underscoring the need for HPV vaccination programs with high population coverage.