Objective: Triage testing is an integral part of high-risk human papillomavirus (HPV)-based cervical screening programs. This study assesses, from a healthcare payer perspective in Singapore, the cost-effectiveness of p16/Ki-67 dual-stained cytology (DS) compared to current standard of care (SOC). Methods: A decision-analytic Markov microsimulation model with a lifetime horizon was built to simulate the outcomes from HPV screening in Singaporean women aged 30–65 years. The intervention (primary testing with HPV genotyping followed by DS reflex test) was compared to current SOC (HPV genotyping followed by cytology) according to Singaporean clinical management guidelines. The progression through health states and associated costs and health outcomes were based on local clinical care data in Singapore. Screening impact was assessed by cost saving, number of colposcopy and quality-adjusted life years (QALYs). Results: Compared to SOC, implementation of HPV genotyping + DS was estimated to decrease the number of screening test (−2.02 times per patient) and colposcopy (−0.16 times per patient), and reduce the overall costs to the Singaporean healthcare system by S$225.59 per patient (95% confidence interval [CI]=S$199.05 to S$249.99). The total QALYs estimates for the 2 approaches were similar (−0.0003; 95% CI=−0.0031 to 0.0022). Sensitivity analyses confirmed the robustness of expected cost-savings and that the full value of avoided colposcopies may be larger than projected in the current analysis. Conclusion This economic modelling analysis projected that using DS instead of conventional cytology as the reflex test for positive test with non-HPV-16/18 subtypes significantly reduced the financial costs of cervical cancer screening in Singapore.