OBJECTIVES: To determine, in a population-based sample of twin pairs, if extra-intestinal symptoms (EIS) are closely associated with both irritable bowel syndrome (IBS) and psychiatric disorders and whether such associations are explained on a genetic basis. METHODS: A random sample of twins between the ages of 44 and 64 years enrolled in the Minnesota Twins Registry completed the Modified Mayo Clinic Bowel Disease Questionnaire, a questionnaire on extra-intestinal symptoms, and the Psychiatric Diagnostic Screening Questionnaire. RESULTS: Of the 3,048 participants (51% response rate), 371 (12.2%) fulfilled Rome II criteria for IBS; 61 (16.4%) had a psychiatric disorder compared with 7.6% (n=204) of those without IBS (P<0.001). In regression analysis both IBS and psychiatric disorders were independently associated with the number of extra-intestinal symptoms (P<0.0005). Concordance rates for high EIS score were 30.0% for monozygote (MZ) twins and 16.7% in dizygote (DZ) twins (P=0.020) and the OR for concordance remained substantially higher for MZ than DZ twins after adjustment for psychiatric disorder and presence of IBS (6.82 (95% CI 4.45-10.45) and 2.71 (95% CI 1.69-4.37)). In MZ twins discordant for IBS, EIS and IBS were significantly associated (P=0.004) and psychiatric disorder and EIS were significantly associated (P=0.001). CONCLUSIONS: Extra-intestinal symptoms are independently associated with both IBS and psychiatric disorders. There is evidence that there is a genetic basis to EIS, but the association with IBS and psychiatric disorders is not primarily explained by genetic influences.