Background: Patient-reported outcomes measures (PROMs) are widely recognized as important tools for achieving a patient-centered approach in health research. While PROMs are subject to several stages of validation during development, even questionnaires with robust psychometric properties may pose problems for targeted patients. Challenges can rise for reasons of clarity, understanding, comfort, or the complexity of the patient’s situation (e.g., their health needs). How can good practices in questionnaire development and validation on one hand, and challenges of accommodating patient comfort and understanding on the other hand be reconciled? Building on the experience of patient engagement in the PriCARE research program, this paper aims to propose: 1) steps to address challenges of patient comfort and understanding of the questionnaires and to reach consensus, and 2) patient-oriented guidelines for administrating the questionnaires. Methods: Based on a participatory approach and the patient engagement framework in the Strategy for Patient-Oriented Research of the Canadian Institutes of Health Research, team members, including patient partners, worked together to discuss the problem, review the questionnaires, and come up with different solutions. Based on literature presenting similar processes in research projects, a working group was created to produce guidelines for administering the questionnaires. We present a step-by-step description of strategies used in PriCARE, to reconcile good research practices for using validated questionnaires and the challenges in questionnaire development related to patient comfort and understanding. Results: This paper demonstrates how patient partners were engaged in PriCARE and integrated into the program’s governance structure, the challenges they raised regarding the questionnaires, and how the challenges were addressed in a six-step approach: 1) Recognizing patient partner concerns, discussing these concerns, and reframing the challenges; 2) Detailing and sharing evidence of the validity of the questionnaires; 3) Evaluating potential solutions; 4) Searching literature for guidelines; 5) Creating guidelines; 6) Sharing and refining guidelines. Conclusion: This six-step approach demonstrates how research teams can integrate patient partners as equal members, develop meaningful collaboration through recognition of individual experiences and expertise, and ensure the patient perspective is taken into consideration in questionnaire research, the development of data collection tools, and healthcare innovation in general.