To date, no studies have evaluated the cost-effectiveness of human papillomavirus (HPV) vaccination in countries in the Extended Middle East and North Africa (EMENA) region. We synthesized population and epidemiologic data for 20 EMENA countries using a model-based approach to estimate averted cervical cancer cases and deaths, disability-adjusted life years (DALYs) and cost-effectiveness ratios (I$ [international dollars] per DALY averted) associated with HPV vaccination of pre-adolescent girls. We utilized additional epidemiologic data from Algeria, Lebanon, and Turkey to evaluate select cervical cancer screening strategies either alone or in combination with vaccination. Results showed that pre-adolescent vaccination of five consecutive birth cohorts at 70% coverage has the potential to prevent over 180,000 cervical cancer cases. Cases averted varied by country, largely due to differences in cancer burden and population size; 69% of cases averted occurred in the three GAVI-eligible countries in EMENA. Despite the low cervical cancer incidence in EMENA, we found that HPV vaccination was cost-effective using a threshold of each country's gross domestic product per capita (a common metric for evaluating cost-effectiveness) in all but five countries at a cost per vaccinated girl of I$25 ($5 per dose). However, cost-effectiveness diminished with increasing vaccine cost; at a cost of I$200 per vaccinated girl, HPV vaccination was cost-effective in only five countries. When the cost per vaccinated girl exceeded I$50 in Lebanon and Turkey and I$150 in Algeria, screening alone was most attractive. We identified opportunities to improve upon current national screening guidelines, involving less frequent screening every 3-5 years. While pre-adolescent HPV vaccination promises to be a cost-effective strategy in most EMENA countries at low costs, decision makers will need to consider many other factors, such as affordability, acceptability, feasibility, and competing health priorities, when making decisions about cervical cancer prevention. This article forms part of a regional report entitled "Comprehensive Control of HPV Infections and Related Diseases in the Extended Middle East and North Africa Region" Vaccine Volume 31, Supplement 6, 2013. Updates of the progress in the field are presented in a separate monograph entitled "Comprehensive Control of HPV Infections and Related Diseases" Vaccine Volume 30, Supplement 5, 2012.