Depression has been shown to moderate the effects of physical illness self-management (ISM) programs. We attempted to replicate these findings for a mental ISM intervention. Outpatients with serious mental illness (N = 428) from eight Tennessee communities were randomly assigned to receive a peer-led self-management intervention called Building Recovery of Individual Dreams and Goals Through Education and Support or services as usual. Psychiatric symptoms were assessed with the Brief Symptom Inventory; the outcome of personal empowerment was measured by the Empowerment Scale. Intent-to-treat analysis using mixed-effects random regression found significant interaction effects between study condition and three moderating symptom profiles. Empowerment was greater for the intervention participants with high levels of depressive symptoms, anxiety symptoms, and general symptom distress than for the experimental participants with low symptom levels and the control subjects with high or low levels of symptoms. These results shed light on how mental ISM programs operate and ways these can be improved.