GARDASIL (Merck & Co., Inc., Whitehouse Station, NJ, USA) is a quadrivalent human papillomavirus (HPV4) vaccine. An epidemiological study was undertaken to evaluate concerns about the potential for HPV4 vaccination to induce serious autoimmune adverse events (SAAEs). The vaccine adverse event reporting system (VAERS) database was examined for adverse event reports associated with vaccines administered from January 2006 through December 2012 to recipients between 18 and 39 years old with a listed residence in the USA and a specified female gender. It was observed that cases with the SAAE outcomes of gastroenteritis (odds ratio (OR) = 4.6, 95 % confidence interval (CI) = 1.3-18.5), arthritis (OR = 2.5, 95 % CI = 1.4-4.3), systemic lupus erythematosus (OR = 5.3, 95 % CI = 1.5-20.5), vasculitis (OR = 4, 95 % CI = 1.01-16.4), alopecia (OR = 8.3, 95 % CI = 4.5-15.9), or CNS conditions (OR = 1.8, 95 % CI = 1.04-2.9) were significantly more likely than controls to have received HPV4 vaccine (median onset of SAAE symptoms from 6 to 55 days post-HPV4 vaccination). Cases with the outcomes of Guillain-Barre syndrome (OR = 0.75, 95 % CI = 0.42-1.3) or thrombocytopenia (OR = 1.3, 95 % CI = 0.48-3.5) were no more likely than controls to have received HPV4 vaccine. Cases with the general health outcomes of infection (OR = 0.72, 95 % CI = 0.27-1.7), conjunctivitis (OR = 0.88, 95 % CI = 0.29-2.7), or diarrhea (OR = 1.01, 95 % CI = 0.83-1.22) were no more likely than controls to have received HPV4 vaccine. Previous case series of SAAEs and biological plausibility support the observed results. Additional studies should be conducted to further evaluate the potential biological mechanisms involved in HPV4 vaccine-associated SAAEs in animal model systems, and to examine the potential epidemiological relationship between HPV4 vaccine-associated SAAEs in other databases and populations.