Background Novel approaches to combating drug-resistant Neisseria gonorrhoeae infections are urgently needed. Targeted therapy with ciprofloxacin has been made possible by a rapid assay for genotyping the gyrase A (gyrA) gene; a nonmutated gene reliably predicts susceptibility to ciprofloxacin. Methods We determined the costs of running the gyrA assay, 500 mg of ciprofloxacin, 250 mg of ceftriaxone injection, and 1000 mg of azithromycin. Cost estimates for gyrA testing included assay reagents and labor. Cost estimates for ceftriaxone included medication, injection, administration, supplies, and equipment. We measured the cost of using the gyrA assay and treatment based on genotype using previously collected data over a 13-month period between November 2015 and November 2016 for all N. gonorrhoeae cases diagnosed at UCLA. We subsequently developed 3 cost models, varying the frequency of testing and prevalence of N. gonorrhoeae infections with ciprofloxacin-resistant or genotype-indeterminate results. We compared those estimates with the cost of recommended 2-drug therapy (ceftriaxone and azithromycin). Results Based on a 65.3% prevalence of cases with ciprofloxacin-resistant or genotype indeterminate N. gonorrhoeae infections when running an average of 1.7 tests per day, the per-case cost of gyrA genotyping and targeted therapy was US $197.19. The per-case cost was US $155.16 assuming a 52.6% prevalence of ciprofloxacin-resistant or genotype-indeterminate infections when running an average of 17 tests per day. The per-case cost of 2-drug therapy was US $142.75. Conclusions Direct costs of gyrA genotyping and targeted ciprofloxacin therapy depend on the prevalence of ciprofloxacin-resistant or genotype-indeterminate infections and testing frequency.