Background: Globally, four curable sexually transmitted infections (STIs) are responsible for over 1-million new infections daily with potential severe complications, predominantly in low- and middle-income countries. South Africa, with high prevalence rates, faces significant challenges and the current syndromic management has limitations such as untreated asymptomatic infections and antibiotic misuse. However, diagnostic tools like GeneXpert for STIs may offer potential improvements. We evaluated costs and cost-effectiveness of reallocating GeneXpert capacity for STI testing in South Africa. Methods: We developed a Microsoft Excel-based static decision analytical model using previously collected data. Over a one-year time horizon, the model compared the costs and outcomes of syndromic management (base case) with nine scenarios using near point-of-care GeneXpert testing for Neisseria gonorrhoeae (NG), Chlamydia trachomatis (CT), and Trichomonas vaginalis (TV) in various target groups, including symptomatic individuals, antenatal care (ANC) attendees, and HIV testers. Outcomes included number of cases treated, cases correctly treated, and reductions in excess antibiotic use and cost-effectiveness analysis as expressed in incremental cost-effectiveness ratios (ICERs) per additional case correctly treated. Univariate deterministic sensitivity analysis assessed parameter uncertainty, and costs were reported in 2024 USD. Results: Total costs, cost per person treated and cost per person correctly treated were lowest in the base case scenario and higher in the near-POC GeneXpert testing scenarios. In the base case, the cost per person treated and correctly treated was $21 and $29 and between $113 and $728 across all GeneXpert testing scenarios. Implementing GeneXpert syndromic testing would cost the healthcare system up to $207 million (+752%), while opportunistic GeneXpert testing scenarios raised costs up to $1.7 billion (+6921%) and targeted or combined GeneXpert testing scenarios cost the healthcare system up to $941 million (+3759%). Of nine scenarios analysed, three were on the cost-effectiveness frontier, resulting in increased total health system costs but higher numbers of cases correctly treated. The ICER (cost per case correctly treated) ranged $429 from $914, with costs increasing up to $1.7 billion (+7094%) and correct diagnoses improving by up to 265%. Sensitivity analysis identified staff cost as the most influential input cost parameter for cost per case correctly treated under the base case scenario. Conclusions: Our study highlights the potential of reallocating excess GeneXpert capacity for STI testing to enhance diagnostic accuracy and improve health outcomes in South Africa. Prioritizing symptomatic individuals and high-risk groups, such as antenatal care attendees, can reduce unnecessary antibiotic use, addressing antimicrobial resistance challenges. These findings support the need for targeted and context-specific strategies to optimize the clinical and economic benefits of GeneXpert deployment for STI management.

The authors have declared no competing interest.

This study was funded by the Foundation for Innovative New Diagnostics (FIND).

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All data produced in the present study are available upon reasonable request to the authors