Purpose: This study aimed to develop and test a structural equation model of health-related quality of life among older women following bilateral total knee replacement based on a literature review and Wilson and Cleary's model of health-related quality of life. Methods: One hundred ninety three women who were diagnosed with osteoarthritis, were older than 65 years, and were between 13 weeks and 12 months of having a bilateral total knee replacement were recruited from an outpatient clinic. Data were collected from July 2017 to April 2018 using a structured questionnaire and medical records. Data were analyzed using SPSS/WIN 22.0, AMOS 22,0, and Smart PLS 3.2.4. Results: The fitness of the hypothetical model was good, with coefficients of determination (R-2) ranging between .28 and .75 and predictive relevance (Q(2)) between .26 and .73. The standardized root mean square residual of the model fit indices for the hypothetical model was .04; which explained 64.2% of physical and 62.5% of mental health-related quality of life. Self-efficacy, symptom status, functional status, and general health perceptions had a significant direct effect on physical health-related quality of life, while social support, symptom status, and general health perceptions had a significant direct effect on participants' mental-health-related quality of life. Conclusion: To improve the physical and mental quality of life of older women who receive bilateral knee replacement, nursing-based intervention strategies that reduce symptoms, improve functional status, and increase health perceptions, self-efficacy, and social support are needed. The most important factor is the symptom status.