Rheumatoid arthritis (RA) diagnosis requires a combination of clinical, laboratory and imaging investigations. The consequences of wrong serology test results are costly: False Positive results (FPs) are initially managed as RA-patients, bringing about extra costs until correct diagnosis is made. The study goals were to: simulate the diagnostic performance of Rheumatoid Factor (RF)-IgA, RF-IgM, and cyclic citrullinated peptides (CCP2), used alone or in multi-testing parallel/sequential combinations; quantify the economic consequences of serology FPs in the United States. 190 established RA patients and 197 controls were used to assess the diagnostic performance of mono-/multi-serology testing. A 12-month Markov model simulated 500,000 RA-suspected individuals tested in Primary Care with mono- or multi-testing. Costs came from the published literature. Uncertainty was addressed with sensitivity analysis. The mono-testing diagnostic performance was: 1=RF-IgA: sensitivity[95%CI]=40.5%[33.5%-47.9%], specificity=92.4%[87.8%-95.7%]; 2=RF-IgM: sensitivity=59.0%[51.6%-66.0%], specificity=89.3%[84.2%-93.3%]; 3=CCP2: sensitivity=59.5%[52.1%-66.5%], specificity=96.5%[92.8%-98.6%]. Defining a “positive result” as “positivity to at least one test” increased sensitivity; “positivity to all the tests” increased specificity: multi-parallel testing: multi.parallel.1) using CCP2+RF-IgM increased specificity to 99.5[97.2-100]; multi.parallel.2) the 3 tests used simultaneously maximized specificity (100[98.1-100]), reducing sensitivity (35.8[29.0-43.1]); multi-sequential testing: testing positive to RF IgA + RF IgM followed by CCP testing led to 90.7[81.7-96.2] sensitivity and to 0[54.1-100.0] specificity. Multi-testing simulation results reduced the number of FPs: mono.1=32,908, mono.2=46,331, mono.3=14,722, multi.1.parallel.1=2,165, multi.parallel.2=0, multi.sequential=0. Multi-testing allowed for important cost savings due to reduced clinical procedures and resource utilization of FPs. In all the scenarios considered, the cost-savings of multi-testing ranged between $9.488.406-$55.032.756-$ compared with CCP mono-testing, and ranged between $56,930,438-$64,521,163 compared with RF-IgM-mono-testing. Simulation results show that multi-serology testing can improve the diagnostic accuracy of serology in RA: the inclusion of CCP2/RF-IgA/RF-IgM individual isotypes minimizes the number of FPs, reducing avoidable costs. Consequently, multi-testing for RA demonstrates superior value from patient and payer perspective.