OBJECTIVE: Managing complex psychiatric disorders like PTSD and bipolar disorder is challenging in Federally Qualified Health Centers (FQHCs) delivering care to U.S residents living in underserved rural areas. This protocol paper describes SPIRIT, a pragmatic comparative effectiveness trial designed to compare two approaches to managing PTSD and bipolar disorder in FQHCs. INTERVENTIONS: Treatment comparators are: 1) Telepsychiatry Collaborative Care, which integrates consulting telepsychiatrists into primary care teams, and 2) Telepsychiatry Enhanced Referral, where telepsychiatrists and telepsychologists treat patients directly. METHODS: Because Telepsychiatry Enhanced Referral is an adaptive intervention, a Sequential, Multiple Assignment, Randomized Trial design is used. Twenty-four FQHC clinics without on-site psychiatrists or psychologists are participating in the trial. The sample is patients screening positive for PTSD and/or bipolar disorder who are not already engaged in pharmacotherapy with a mental health specialist. Intervention fidelity is measured but not controlled. Patient treatment engagement is measured but not required, and intent-to-treat analysis will be used. Survey questions measure treatment engagement and effectiveness. The Short-Form 12 Mental Health Component Summary (SF-12 MCS) is the primary outcome. RESULTS: A third (34%) of those enrolled (n=1004) are racial/ethnic minorities, 81% are not fully employed, 68% are Medicaid enrollees, 7% are uninsured, and 62% live in poverty. Mental health related quality of life (SF-12 MCS) is 2.5 standard deviations below the national mean. DISCUSSION: We hypothesize that patients randomized to Telepsychiatry Collaborative Care will have better outcomes than those randomized to Telepsychiatry Enhanced Referral because a higher proportion will engage in evidence-based treatment.