The heightened risk of persons with serious mental illness to contract and transmit human immunodeficiency virus (HIV) is a public health problem. Here we evaluate the interaction between psychiatric diagnosis and response to a community based-intervention targeted at treatment adherence in 236 HIV+ persons with co-occurring mental illness. To examine differential effectiveness of the intervention for categories of patient diagnosis, we reanalyzed the data after stratifying participants into two diagnostic groups: (1) participants with depressive disorders without psychosis and (2) participants with a psychotic or bipolar disorder. Outcomes included viral load and mental health quality of life (SF-12 Mental Health). We found that HIV+ persons with non-psychotic depressive disorders demonstrated a larger decrease in HIV viral load and more improvement in measures of mental health quality of life when compared to HIV+ persons with psychotic and bipolar disorders. We suggest that successful adherence interventions should be informed by psychiatric symptomatology.