OBJECTIVES: The objective of this paper is to describe the complex mixed-methods design of a study conducted to assess health-related quality of life (HRQOL) outcomes and ostomy-related obstacles and adjustments among long-term (>5 years) colorectal cancer (CRC) survivors with ostomies (cases) and without ostomies (controls). In addition, details are provided regarding the study sample and the psychometric properties of the quantitative data collection measures used. Subsequent manuscripts will present the study findings. RESEARCH DESIGN AND METHODS: The study design involved a cross-sectional mail survey for collecting quantitative data and focus groups for collecting qualitative data. The study subjects were individuals identified as long-term CRC survivors within a community-based health maintenance organization’s enrolled population. Focus groups comprised of cases were conducted. The groups were divided by gender and HRQOL high and low quartile contrasts (based on the mail survey data). MAIN OUTCOME MEASURES: The modified City of Hope Quality of Life (mCOH-QOL)-Ostomy and SF-36v2 questionnaires were used in the mail survey. An abridged version of the mCOH-QOL-Ostomy was used for the control subjects. Focus groups explored ostomy-related barriers to self-care, adaptation methods/skills, and advice for others with an ostomy. RESULTS: The survey response rate was 52% (679/1308) and 34 subjects participated in focus groups. The internal consistency reliability estimates for the mCOH-QOL-Ostomy and SF-36v2 questionnaires were very acceptable for group comparisons. In addition, evidence supports the construct validity of the abridged version of the mCOH-QOL-Ostomy. Study limitations include potential non-response bias and limited minority participation. CONCLUSIONS: We were able to successfully recruit long-term CRC survivors into this study and the psychometric properties of the quantitative measures used were quite acceptable. Mixed-methods designs, such as the one used in this study, may be useful in identification and further elucidation of common problems, coping strategies, and HRQOL outcomes among long-term cancer survivors.