Objective: To assess the impact of the human immunodeficiency virus (HIV) on the pathogenesis of human papillomavirus (HPV) infection, precancerous lesions, invasive cervical cancer, and total treatment costs in South African women. Invasive cervical cancer is the second most common cancer among South African women. The high prevalence of HIV in South Africa (18%) is likely a contributing factor to the high rates of cervical cancer, as immunocompromised patients are at higher risk of HPV infection and associated precancerous lesions. Methods: We developed a lifetime Markov simulation model of the natural history of cervical neoplasia and HIV infection. The model was used to predict the impact of HIV and acquired immunodeficiency syndrome (AIDS)-related mortality on the course of cervical disease in a hypothetical cohort of 100,000 South African women. Clinical data were based on published South African literature, high-quality clinical studies, and expert opinion. Risk of progression of HIV/AIDS was based on CD4 cell counts and viral load levels. Primary outcome measures included lifetime risk of cervical intraepithelial neoplasia and cervical cancer, years of life saved, quality-adjusted life years saved (QALYs), and total lifetime costs. Results: Lifetime risk of cervical cancer ranged from 2.3% among HIV-negative women to 3.3% in HIV-positive women. In a cohort of 100,000 women, the high rate of HIV infection in South Africa led to an additional 5,200 HPV infections, 490 cervical cancers, and 175 cervical cancer deaths. HIV infection decreased average life expectancy among South African women by 3.31 years or 3.28 QALYs and increased costs by approximately Rand21,400 per woman. Conclusion: HIV infection contributes to higher rates of invasive cervical cancer and increases costs. Given the high prevalence of HIV infection in South Africa, more frequent cervical cancer screening for HIV-positive women may be warranted.