Abstract Background The World Health Organization recommends a 1- or 2-dose human papillomavirus (HPV) vaccination schedule for females aged 9 to 20 years. Studies confirming the efficacy of a single dose and vaccine modifications are needed, but randomized controlled trials are costly and face logistical and ethical challenges. We propose a resource-efficient single-arm trial design that uses untargeted and unaffected HPV types as controls. Methods We estimated HPV vaccine efficacy (VE) from a single arm by comparing 2 ratios: the ratio of the rate of persistent incident infection with vaccine-targeted HPV 16 and 18 (HPV 16/18) and cross-protected types HPV 31, 33, and 45 (HPV 31/33/45) to vaccine-unaffected types HPV 35, 39, 51, 52, 56, 58, 59, and 66 (HPV 35/39/51/52/56/58/59/66) vs the ratio of prevalence of these types at the time of trial enrollment. We compare VE estimates using only data from the bivalent HPV 16/18 vaccine arm of the Costa Rica Vaccine Trial with published VE estimates that used both the vaccine and control arms. Results Our single-arm approach among 3727 women yielded VE estimates against persistent HPV 16/18 infections similar to published 2-arm estimates from the trial (according-to-protocol cohort: 91.0% , 95% CI = 82.9% to 95.3% single-arm vs 90.9% , 95% CI = 82.0% to 95.9% 2-arm; intention-to-treat cohort: 41.7%, 95% CI = 32.4% to 49.8% single-arm vs 49.0% , 95% CI = 38.1% to 58.1% 2-arm). VE estimates were also similar in analytic subgroups (number of doses received; baseline HPV serology status). Conclusions We demonstrate that a single-arm design yields valid VE estimates with similar precision to a randomized controlled trial. Single-arm studies can reduce the sample size and costs of future HPV vaccine trials while avoiding concerns related to unvaccinated control groups. Trial registration ClinicalTrials.gov Identifier: NCT00128661.