Background: Primary open-angle glaucoma (POAG) is the most common subtype of glaucoma. We evaluate the cost-effectiveness of polygenic risk score (PRS) profiling as a screening tool for POAG. Methods: We used a Markov cohort model to evaluate the cost-effectiveness of implementing PRS screening in the UK and Australia, conducted from the healthcare payer’s perspective. We used published data to calculate prevalence, transition probabilities, utility, cost and other parameters in the model. Our main outcome measure was the incremental cost-effectiveness ratio (ICER) and secondary outcomes were years of blindness avoided and a ‘Blindness ICER’. We did one-way as well as two-way deterministic and probabilistic sensitivity analyses. Results: The proposed screening programme for POAG in the UK is predicted to result in ICER of £24,783 (95% CI: £13,373–66,960) and would avoid 1 year of blindness at ICER of £10,095 (95% CI: £5513–27,656). In Australia, it is predicted to result in ICER of AU$34,252 (95% CI: AU$21,324–95,497) and would avoid 1 year of blindness at ICER of AU$13,359 (95% CI: AU$8143–37,448). Using the willingness to pay thresholds of $54,808 and £30,000, the proposed screening model is 79.2% likely to be cost-effective in Australia and is 60.2% likely to be cost-effective in the UK, respectively. Conclusion: We describe and model the cost-efficacy of incorporating a polygenic risk score for POAG screening in Australia and the UK for the first time and results indicated this is a promising cost-effectiveness strategy.