Introduction Oncogenic human papillomavirus (HPV) types 16 and 18 pose the greatest risk for cervical cancer. Infection with HPV types 16 and 18, which cause 70% of cervical cancer worldwide, could be prevented with commercially available HPV 16 and 18 vaccines. A previous study in South Africa demonstrated that vaccination of 12 year old girls with a HPV vaccine, prior to sexual debut, is cost effective, however this was carried out prior to the roll-out of the HPV vaccination program. The aim of this study is to provide an up-dated cost effectiveness analysis of HPV 16 and 18 vaccination of nine year old school girls in South Africa, from a public sector healthcare provider perspective. Methods Treeage Pro Suite® software was used to create a lifetime static Markov model, to determine the cost effectiveness of a school based vaccination program in the public sector compared to cervical cancer screening alone. The time horizon was based on average life expectancy of 61 years of females in South Africa. The costs and effects of vaccination, screening and treatment compared to screening and treatment of precancerous lesions and cervical cancer were modelled with data obtained from published literature. Expert opinion was sought, where no published data was available. Cost and effects were discounted by 5% and a one way sensitivity analysis was performed on a range of parameters. Results Results of this study showed that HPV vaccination was more cost effective than screening alone. The incremental cost-effectiveness ratio (ICER) of adding HPV vaccination to the existing screening program was R10 567.79, and dominant for the HPV vaccination compared to screening alone from a public sector payer perspective. The cost estimate of a two-dose schedule, school based HPV vaccination, is R636.75 per vaccinated girl. The vaccination cost to avert one case of cervical cancer stage 1 due to HPV 16 and/or 18 is R58 581.92 and over a lifetime, the number of new cervical cancer stage 1 cases averted due to HPV 16 and 18 vaccination of 507 073 nine year old girls is 5 538. The ICER for the exploratory model of HPV vaccination of HIV-infected nine year old girls also showed that HPV vaccine strategy with dominant with ICER of R2 375.62 per QALY. Conclusions A school based vaccination program of girls, prior to sexual debut, is a cost effective strategy to reduce the risk of cervical cancer when compared to screening alone in the public healthcare sector.