BACKGROUND: Most interventions for conditions with a small cohort size, such as transplantation, are unlikely to be part of a clinical trial. When condition-specific evidence is lacking, expert consensus can offer more precise guidance to improve care. Management of cardiovascular risk in liver-transplant recipients is one example for which clinicians have, to date, adapted evidence-based guidelines from studies in the general population. However, even when consensus is achieved, implementation of practice guidance is often inadequate and protracted. We report on a novel mixed-methods approach, the Northwestern Method©, for the development of clinical-practice guidance when condition-specific evidence is lacking. We illustrate the method through the development of practice guidance for managing cardiovascular risk in liver-transplant recipients. METHODS: The Northwestern Method© consists of (i) adaptation of relevant, existing, evidence-based clinical-practice guidelines for the target population; (ii) consensus by experts of the proposed practice guidance; (iii) identification of barriers to guidance adherence in current practice; and (iv) recommendation for implementation and dissemination of the practice guidance. The method is based on an iterative, user-centered approach in which the needs, wants, and limitations of all end users, including patients, are attended to at each stage of the design and development process. CONCLUSIONS: The Northwestern Method© for clinical-practice-guidance development uses a mixed-methods approach to bring together broad representation from multiple disciplines and practice settings to develop consensus considering the unique needs and preferences of patients, caregivers, and practitioners who are directly impacted by clinical-practice-guidance recommendations. We hypothesize that a priori involvement of end users in the guidance-development process will lead to sustainable implementation of guidance statements into clinical practice.