<p>Summary of modelled scenarios.</p>

South Africa has high sexually transmitted infections (STIs) prevalence and currently implements syndromic management, which has limitations including untreated asymptomatic infections and excess antibiotic use. Diagnostic tools like GeneXpert may offer potential improvements. We evaluated potential costs and benefits of GeneXpert for STIs testing. We developed a static analytical model using existing data over a one-year time horizon (January-December 2024) from a provider perspective. We estimated costs (2024 USD), outcomes, cost-effectiveness, and budget impact of syndromic management and multiple near point-of-care (i.e., off-site laboratory) GeneXpert testing scenarios for Neisseria gonorrhoeae, Chlamydia trachomatis, and Trichomonas vaginalis. Target groups included symptomatic individuals, antenatal care (ANC) attendees, and HIV testers. Deterministic sensitivity analysis was conducted on key parameters. Cost per person, and per person correctly diagnosed and treated ranged from $21-$29 under syndromic management and $88-$755 in GeneXpert scenarios. Syndromic management cost the healthcare system an estimated $24.1 million per year; symptomatic GeneXpert testing would cost substantially more: $102.1-$207.8 million, and $300.9 million-$2.1 billion for GeneXpert scenarios involving symptomatic individuals, ANC attendees, and HIV testers. GeneXpert testing reduces excess antibiotic use by up to 88% compared to syndromic management. Of scenarios modelled, three were on the cost-effectiveness frontier: syndromic management, S4: symptomatic adults and adolescent girls and young women HIV testers, and S8: symptomatic adults, ANC attendees and HIV testers. While syndromic management was least costly, incremental cost per additional person correctly diagnosed and treated was $863 (S4) and $1,064 (S8). These scenarios would cost $3.5 and $12.0 billion over 5-years, respectively, compared to $146.0 million in syndromic management. Staff and diagnostic cost were the most influential parameter in sensitivity analysis. Prioritizing GeneXpert testing for symptomatic individuals and high-risk groups (e.g., HIV testers) can improve STI management but requires additional investment. These findings support the need for targeted strategies to optimise STI control.