A health-related quality of life (HRQOL) measure for multiple sclerosis (MS) was developed to address the need for assessing HRQOL in clinical effectiveness and quality of care research, especially for chronic diseases. The study combined a generic HRQOL instrument, the RAND 36-Item Health Survey (SF-36), with disease-specific items relevant to MS. The final measure, the Multiple Sclerosis Quality of Life (MSQOL)-54 Instrument, consists of 52 items across 12 scales and two single items. It includes items addressing health distress, sexual function, cognitive function, energy, pain, and social function. Internal consistency reliability estimates for the 12 scales ranged from 0.75 to 0.96, and test-retest intraclass correlation coefficients ranged from 0.66 to 0.96. Exploratory factor analysis confirmed two underlying dimensions: physical health and mental health. Construct validity was supported by significant associations between MSQOL-54 scales and symptom severity, ambulation, employment limitations, hospitalization, and depressive symptoms. The study aimed to develop a self-report measure that combines the strengths of generic and disease-specific approaches. The MSQOL-54 was developed using a consecutive series of 231 adults with definite MS, confirmed by experts. The SF-36 was selected as the generic core due to its breadth and depth of coverage of HRQOL domains and availability of data for the general US population. The MSQOL-54 was evaluated on psychometric criteria, including feasibility, variability, reliability, reproducibility, and construct validity. The measure allows comparisons of HRQOL in MS with other diseases and the general population, as well as within-disease comparisons. The study highlights the importance of HRQOL measures in understanding the impact of MS on patients' lives and in guiding healthcare decisions.A health-related quality of life (HRQOL) measure for multiple sclerosis (MS) was developed to address the need for assessing HRQOL in clinical effectiveness and quality of care research, especially for chronic diseases. The study combined a generic HRQOL instrument, the RAND 36-Item Health Survey (SF-36), with disease-specific items relevant to MS. The final measure, the Multiple Sclerosis Quality of Life (MSQOL)-54 Instrument, consists of 52 items across 12 scales and two single items. It includes items addressing health distress, sexual function, cognitive function, energy, pain, and social function. Internal consistency reliability estimates for the 12 scales ranged from 0.75 to 0.96, and test-retest intraclass correlation coefficients ranged from 0.66 to 0.96. Exploratory factor analysis confirmed two underlying dimensions: physical health and mental health. Construct validity was supported by significant associations between MSQOL-54 scales and symptom severity, ambulation, employment limitations, hospitalization, and depressive symptoms. The study aimed to develop a self-report measure that combines the strengths of generic and disease-specific approaches. The MSQOL-54 was developed using a consecutive series of 231 adults with definite MS, confirmed by experts. The SF-36 was selected as the generic core due to its breadth and depth of coverage of HRQOL domains and availability of data for the general US population. The MSQOL-54 was evaluated on psychometric criteria, including feasibility, variability, reliability, reproducibility, and construct validity. The measure allows comparisons of HRQOL in MS with other diseases and the general population, as well as within-disease comparisons. The study highlights the importance of HRQOL measures in understanding the impact of MS on patients' lives and in guiding healthcare decisions.