Model Input Base Case Values.

Testing for high-risk human papillomavirus with genotyping for types 16 and 18 (HPV16/18) and triage by p16/Ki-67 dual-stain immunocytochemistry improves diagnostic performance in cervical cancer screening. We estimated the cost-effectiveness of HPV DNA–based primary screening strategies that detect high-risk genotypes every 5 years with either reflex cytology (hrHPV–Pap-5) or reflex dual stain (CINtec® PLUS, Roche; hereafter hrHPV–CINtec-5) versus cytology every 3 years (SoC (PAP-3)) among women aged 25–64 years, from the Chilean public healthcare perspective. A state-transition microsimulation reflected the natural history of cervical cancer in screening-eligible Chilean women, using local epidemiology and literature-informed inputs. Direct medical costs were obtained from official Chilean sources and converted to USD (1 USD = 938 CLP). Deterministic and probabilistic sensitivity analyses were conducted; a 30–64 years initiation scenario was also evaluated. Both high-risk HPV DNA-based strategies were more effective and cost-saving than SoC (PAP-3). In the 25–64 base case, hrHPV–CINtec-5 yielded the greatest health gain (13,003 incremental Quality-Adjusted Life Year, hereafter QALYs) with $16.65 saved per woman, while hrHPV–Pap-5 saved $32.57 with 12,844 QALYs. Probabilistic sensitivity analysis confirmed dominance (most simulations in the southeast quadrant) and cost-effectiveness acceptability >90% across willingness-to-pay ranges. Deterministic analysis highlighted progression risk from HPV16/18 and the discount rate as key drivers. Transitioning from PAP-3 to high-risk HPV DNA-based primary screening in Chile is projected to improve health outcomes while reducing costs. Among HPV DNA-based strategies detecting high-risk genotypes evaluated, triage with hrHPV–CINtec-5 provided the largest health gain while remaining cost-saving; hrHPV–Pap-5 maximized cost savings. These findings support modernizing the national screening program.