Some patients with diarrhea-predominant irritable bowel syndrome (IBS-D) may have undiagnosed celiac sprue (CS). Because the symptoms of CS respond to a gluten-free diet, testing for CS in IBS may prevent years of morbidity and attendant expense. We sought to determine whether this might be a cost-effective diagnostic strategy in IBS-D.We used decision analysis to calculate the cost-effectiveness of 2 competing strategies in IBS-D: (1) start empirical IBS treatment and (2) perform serologic test for CS followed by endoscopic biopsy for positive tests. The base-case cohort had a CS prevalence of 3.4%, which was varied between 0% and 100% in sensitivity analysis. The outcome measure was cost per symptomatic improvement.Under base-case conditions, testing for CS instead of starting empiric IBS therapy cost an incremental $11,000 to achieve one additional symptomatic improvement. Testing for CS became the dominant strategy when the prevalence of CS exceeded 8%, the specificity of CS testing exceeded 98%, or the cost of IBS therapy exceeded $130/month. The incremental cost-effectiveness of testing for CS exceeded $50,000 when the prevalence fell below 1%.Testing for CS in patients with IBS-D has an acceptable cost when the prevalence of CS is above 1% and is the dominant strategy when the prevalence exceeds 8%. The decision to test should be based on a consideration of the population prevalence of underlying CS, the operating characteristics of the screening test employed, and the cost of proposed therapy for IBS.