Aims and objectives: To test whether the revised Wilson and Cleary model could identify which factors contribute to health-related quality of life in chronic kidney disease. Background: Chronic kidney disease affects a person's health-related quality of life detrimentally although nursing practice informed by theory is only beginning to emerge. Design: A cross-sectional study reported using the STROBE guidelines. Methods: About 886 participants with chronic kidney disease (varying grades) completed validated measures of symptoms (renal version of the Integrated Palliative care Outcome Scale), and general health perceptions and health-related quality of life (European Quality of Life five-dimension three-level). Socio-demographic and renal characteristics were also collected. Data were analysed using descriptive statistics and structural equation modelling. Results: Biological function (decreased kidney function and haemoglobin and greater number of comorbidities), directly contributed to increased symptom burden. Symptoms demonstrated strong negative relationships with both general health perceptions and health-related quality of life. General health perceptions had a direct positive relationship with health-related quality of life. As age increased, health-related quality of life decreased. The only environmental characteristic of significance was the distance between home and hospital although it was not directly associated with health-related quality of life. Overall, the model explained approximately half of the deterioration in health-related quality of life. Conclusions: The model demonstrated how various factors influence alteration of health-related quality of life in people with chronic kidney disease. Early identification of these factors could assist nurses to introduce effective management strategies into patient care plans proactively. Relevance to clinical practice: Comprehensive symptom assessment needs to occur not only in kidney failure but in earlier chronic kidney disease grades to enable timely interventions targeted at improving people's wellbeing. Patient or public contribution: Validated interviewer administered questionnaires were completed by participants with chronic kidney disease in this study.