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Objective Evaluation of the long-term HPV-16/18 AS04-adjuvanted vaccine immunogenicity persistence in women. Design Multicentre, open-label, long-term follow-up (NCT00947115) of a primary phase–III study (NCT00196937). Setting Six centres in Germany and Poland. Population 488 healthy women (aged 15–55 years, age-stratified into groups: 15–25, 26–45, and 46–55 years) who received three vaccine doses in the primary study. Methods Immune responses were evaluated in serum and cervicovaginal secretion (CVS) samples 6 years after dose 1. Anti-HPV-16/18 geometric mean titres (GMTs) were measured by enzyme-linked immunosorbent assay (ELISA), and were used to fit the modified power-law and piecewise models, predicting long-term immunogenicity. Serious adverse events (SAEs) were recorded. Main outcome measures Anti-HPV-16/18 seropositivity rates and GMTs 6 years after dose 1. Results At 6 years after dose 1, all women were seropositive for anti-HPV–16 and ≥97% were seropositive for anti-HPV–18 antibodies. GMTs ranged from 277.7 to 1344.6 EU/ml, and from 97.6 to 438.2 EU/ml, for anti-HPV–16 and anti-HPV–18, respectively. In all age groups, GMTs were higher (anti-HPV–16, 9.3–45.1-fold; anti-HPV–18, 4.3–19.4-fold) than levels associated with natural infection (29.8 EU/ml). A strong correlation between serum and CVS anti-HPV-16/18 levels was observed, with correlation coefficients of 0.81–0.96 (anti-HPV–16) and 0.69–0.84 (anti-HPV–18). Exploratory modelling based on the 6–year data predicted vaccine-induced anti-HPV-16/18 levels above natural infection levels for at least 20 years, except for anti-HPV–18 in the older age group (piecewise model). One vaccine-related and two fatal SAEs were reported. Conclusions At 6 years after vaccination, immune responses induced by the HPV-16/18 AS04-adjuvanted vaccine were sustained in all age groups.