This study was designed to answer the question of whether a cervical cancer prevention programme that incorporates a human papillomavirus (HPV) vaccine is potentially more cost-effective than the current strategy of screening alone in South Africa. We developed a static Markov state transition model to describe the screening and management of cervical cancer within the South African context. The incremental cost-effectiveness ratio of adding HPV vaccination to the screening programme ranged from US $1078 to 1460 per quality-adjusted life year (QALY) gained and US$3320–4495 per life year saved, mainly depending on whether the study was viewed from a health service or a societal perspective. Using discounted costs and benefits, the threshold analysis indicated that a vaccine price reduction of 60% or more would make the vaccine plus screening strategy more cost-effective than the screening only approach. To address the issue of affordability and cost-effectiveness, the pharmaceutical companies need to make a commitment to price reductions.