OBJECTIVE To compare the effectiveness of serotonin reuptake inhibitors (SSRIs) and tricyclic antidepressants (TCAs) for anxiety and mood disorders in a naturalistic setting. METHODS 114 of 2,000 outpatients drawn from a private facility with a diagnosis of mood or anxiety disorder had two separate episodes during which they were treated once with a SSRI and once with a TCA. The drugs had to be in monotherapy and appropriate according to the recent guidelines. Key outcome measures included several rating scales, the results of which were combined into three measures of outcome: full response (no symptom), partial response (residual symptoms), poor response. RESULTS TCAs produced a better response in 63 cases and SSRIs in 18 cases (p < 0.00001). When the outcome was dichotomized, TCAs were still superior (stricter criterion of full response: p = 0.0002; lower threshold: p < 0.0001). Considering depressive and anxiety disorders separately, TCAs remained superior in terms of efficacy (for depression: p < 0.0001; for anxiety: p = 0.026). Moreover, the second episode of illness showed a better outcome than the first (p = 0.0008). CONCLUSIONS In those cases where two different antidepressants were prescribed over two different episodes of illness, TCAs were significantly more effective than SSRIs, regardless of the type of disorder and order of prescription.