INTRODUCTION Understanding the mode of action of adjuvants is important for the interpretation of clinical studies. AREAS COVERED This paper discusses how the results of GSK's clinical studies with an AS04-adjuvanted human papillomavirus (HPV) vaccine are supported by the mode of action of AS04. AS04 and antigens must be injected at the same intramuscular site together or within 24 h of each other. AS04 induces local cytokine production leading to increased recruitment of dendritic cells and monocytes and raised numbers of antigen presenting cells in the draining lymph node. The localized and transient nature of the innate immune response supports the acceptable safety profile observed in clinical studies. The readers will gain a comprehensive understanding of the mode of action of AS04 and how it relates to results of clinical studies. EXPERT OPINION The AS04-adjuvanted HPV vaccine has an acceptable safety profile and induces an enhanced and sustained immune response and high protection against HPV types 16/18. Cross-protection against oncogenic HPV types 31/33/45 not contained in the vaccine is also observed. The mode of action of AS04 supports the clinical profile of the AS04-adjuvanted HPV vaccine.