Human papillomavirus (HPV) infections and associated diseases, such as genital warts and cervical cancer, cause a significant burden to patients and the healthcare system in South Africa.

Based on a Markov model, we found that nonavalent HPV vaccination is cost effective compared with bivalent HPV vaccination (incremental cost-effectiveness ratio [ICER]: South African Rand (R) 13,013 per quality-adjusted life-year [QALY]) for 9- to 14-year-old girls at the South African willingness-to-pay threshold of R23,630 per QALY.

Targeted policies aimed at improving vaccination coverage rates are substantial to further reduce ICERs for HPV vaccines in South Africa.