Objective: A single previous paper on this topic found a direct pathway between cognitive behavioral therapy (CBT) and an irritable bowel syndrome (IBS) global symptom score. This is controversial since under the biopsychosocial model, the expectation is that CBT's effect would be mediated by mood. Using more sensitive bowel symptom scales and measurements at additional time points, we aimed to compare the relative strengths of direct pathways between CBT and change in IBS symptoms and indirect pathways that operate via mood state using structural equation modeling. Methods: Our data set included 105 people with Rome I IBS randomized to individual CBT (n=34), relaxation therapy (n=36), and usual medical care (n=35). The primary outcome was defined as adequate relief of IBS symptoms in terms of the distress, frequency, and impairment according to the Bowel Symptom Severity Scale. Outcomes in functional status (according to the 36-item Short-Form Health Survey) and psychological status (Hospital Anxiety and Depression Scale) were secondary outcomes. Results: Our data suggest indirect pathways that operate via mood, most clearly anxiety but to a lesser extent depression. Statistically significant pathways were identified that lead from CBT to change in mood state thence to change in bowel symptoms, followed by further changes in mood then changes in bowel symptoms. Our data provide no evidence of direct effect of CBT on bowel symptoms. Conclusions: The present study suggests that CBT may operate via changes in mood state while not ruling out the possibility of direct effects. Our findings do not directly support, but are consistent with, a biopsychosocial model.