Objective: There is a paucity of randomized controlled trials (RCTs) to evaluate models of palliative care. Although interventions vary, all have faced a variety of methodological challenges including adequate recruitment, missing data, and contamination of the control group. We describe the ENABLE II intervention, methods, and sample baseline characteristics to increase intervention and methodological transparency, and to describe our solutions to selected methodological issues. Methods: Half of the participants recruited from our rural U.S.comprehensive cancer center and affiliated clinics were randomly assigned to a phone-based, nurse-led educational, care coordination palliative care intervention model. Intervention services were provided to half of the participants weekly for the first month and then monthly until death, including bereavement follow-up call to the caregiver. The other half of the participants were assigned to care as usual. Symptoms, quality of life, mood, and functional status were assessed every 3 months until death. Results: Baseline data of 279 participants were similar to normative samples. Solutions to methodological challenges of recruitment, missing data, and "usual care" control group contamination are described. Significance of results: It is feasible to overcome many of the methodological challenges to conducting a rigorous palliative care RCT. © 2009 Cambridge University Press.