BACKGROUND: Irritable bowel syndrome (IBS) is a common gastrointestinal disorder seen by both primary care providers (PCPs) and gastroenterologists, and further diagnostic testing is generally discouraged unless red-flag symptoms are present. AIMS: Examine if advanced serologic testing for chronic abdominal pain in IBS patients followed society-specific guidelines and evaluate the diagnostic accuracy of these tests. METHODS: The study involved a retrospective cross-sectional analysis of adults aged 18 and older who were seen at our institution between 2013 and 2018. Tests included: C1 esterase inhibitor, MEFV gene, urine porphobilinogen, anti-dsDNA, and heavy metal screening. Patients with preexisting rheumatological conditions or diagnoses such as hereditary angioedema, porphyria, familial Mediterranean fever, or lead poisoning were excluded. An appropriateness scale based on disease-specific guidelines was used to evaluate test suitability. RESULTS: Among 26,732 IBS patients, 143 underwent advanced laboratory testing, with 85.3% ordered by gastroenterologists. Only 12.5% of tests adhered to society-specific guidelines, and the positive test rate was 2.1%. The total cost of testing was 6,542, with 9,007 spent on tests deemed inappropriate. CONCLUSIONS: The findings emphasize the effectiveness and importance of adhering to Rome IV criteria, as advanced testing often fails to improve diagnostic accuracy and increases unnecessary healthcare costs.