Rotavirus gastroenteritis (RVGE) has an important health and economic burden, particularly in low-and middle-income countries. In response to this public health challenge, the World Health Organization recommended the implementation of rotavirus vaccination globally in 2009. The deployment of live oral rotavirus vaccines for infants has proven effective in reducing the morbidity and mortality associated with RVGE, albeit with varying degrees of effectiveness across different nations. However, concerns have arisen regarding its potential association with intussusception, a rare type of bowel obstruction, in certain contexts. Afghanistan introduced the monovalent rotavirus vaccine, ROTARIX, in January 2018, targeting infants at six and ten weeks of age. Following its rollout, active post-licensure hospital-based surveillance was initiated from May 2018 to June 2022, focusing on monitoring the safety and effectiveness of ROTARIX among Afghan children <5 years old. This surveillance endeavour presented an opportune moment to evaluate whether the benefits of rotavirus vaccination outweigh the associated risks and whether the accrued advantages justified the incremental costs incurred. This Doctor of Public Health (DrPH) thesis aims to assess the real-world benefit-risk and cost-utility of monovalent rotavirus vaccination in Afghanistan. Leveraging the UNIVAC decision-support model, a static proportionate outcomes cohort model, vaccine benefits (numbers of averted RVGE cases, clinic visits, hospital admissions, and fatalities among children aged <5 years), vaccine risks (potential numbers of excess intussusception hospital admissions and deaths) and associated costs, were calculated with and without rotavirus vaccination, from 2018 to 2024. Primary outcomes were the cost-utility ratio (US$ per DALY averted) and benefit-risk ratio (excess intussusception deaths per RVGE death averted). To inform future decision-making regarding rotavirus vaccination strategies, a separate analysis compared the cost-utility of four alternative rotavirus vaccine options – ROTARIX® (1 dose vial), ROTASIIL (1 dose vial), ROTASIIL (2 dose vial), and ROTAVAC (5 dose vial) – over a decade-long period (2025-2034). Data regarding vaccine effectiveness and safety were derived from post-marketing surveillance, utilizing test-negative case-control and self-controlled case-series analyses, respectively. Supplementary inputs were drawn from a national household survey, the scientific literature, and international databases. This research concludes that the rotavirus vaccine is a beacon of hope in combating rotavirus diseases in Afghanistan. Its effectiveness, impact, safety, and cost-effectiveness, when considered with the contextual factors, strongly support the continuation of the rotavirus vaccination in Afghanistan. The findings from this study support the sustained implementation of rotavirus vaccination in Afghanistan. The results have been widely disseminated through various channels, such as scientific conferences, presentations, and scholarly publications. KEYWORDS: Rotavirus; Rotavirus vaccine; Effectiveness; Safety; Benefit-risk; Cost-utility; Surveillance; Afghanistan.