Enrolling adequate numbers of subjects to research projects that focus on the supportive needs of patients and caregivers is difficult, and this difficulty significantly impedes investigation of this important research area. We report reasons that patients or their informal caregivers declined to participate in one of two randomized, longitudinal clinical trials testing the Comprehensive Health Enhancement Support System (CHESS), a Web-based information and support scheme for people with advanced cancer and their primary informal caregivers. Patients were asked why they declined participation in these trials; their responses then were recorded and coded into themes. The leading reasons included factors related to using a computer (eg, lack of familiarity with using this technology, access to other resources), being attended to by a caregiver (eg, poor caregiver health, caregiver burden, patient doing well and not needing a caregiver), taking part in a study (eg, survey burden, privacy concerns, wording of the consent form), dealing with personal issues (eg, time commitment, timing of study, feelings of being overwhelmed, and coping styles), and lack of interest. By using eligibility criteria that largely parallel those for studies of chemotherapeutic regimens, this research project highlighted reasons why subjects decline participation in clinical trials. This information was specific to supportive care trials; it may help researchers plan recruitment strategies and enrollment targets.