BACKGROUND: A conceptual model approach to clarify the elements of health-related quality of life (HRQL), their determinants and causal pathways is needed to aid researchers, health practitioners and policy makers in their bid to improve HRQL outcomes in patients. The aim of this systematic review was to appraise empirical evidence on the performance of the Wilson and Cleary Model of HRQL. METHODS: We conducted a search of MEDLINE, Science Direct, PsyARTICLES and CINAHL databases to identify articles that used Wilson and Cleary model to examine HRQL in chronic diseases. A narrative synthesis was employed in the review of the articles. RESULTS: Evidence supports linkages between adjacent concepts and between non-adjacent concepts of the Wilson and Cleary model indicating that in practice there is a need to examine relationships among constructs - or to consider interventions in terms of - both with and without mediators. Symptoms status has the highest magnitude of relative impact on health-related quality of life. CONCLUSION: The Wilson and Cleary model demonstrated good features suitable for evaluating health-related quality of life in chronic diseases.