Background: Health-related quality of life (HRQoL) is an important outcome measure in chronic diseases like rheumatoid arthritis (RA). However, there is a paucity of literature from mainland China on HRQoL and factors that influence it in people with RA. Objectives: The aim of this study was to assess HRQoL and to determine which factors, based on the Wilson and Cleary model, contribute to the prediction of HRQoL among persons with RA in mainland China. Methods: A cross-sectional design was used. Persons with RA (N = 207) were recruited from the outpatient clinics of a university-affiliated hospital in central China. Participants responded to a demographic data questionnaire, the Medical Outcomes Study 36-Item Short Form Health Survey (SF-36), the Multidimensional Fatigue Inventory, the Health Assessment Questionnaire-Disability Index, the eight-item Arthritis Self-Efficacy Scale, and the Medical Outcomes Study Social Support Survey. Structural equation modeling was used to estimate the effects of factors from the Wilson and Cleary model on HRQoL. Results: Scores on all SF-36 subscales were significantly lower in patients with RA compared with a general Chinese sample. Lower self-efficacy, greater fatigue, greater functional disability, lower social support, being unemployed, higher disease activity, more comorbidities, lower income level, being female, living in rural settings, and being older were directly or indirectly significantly and negatively associated with HRQoL; 67% of the total variance of HRQoL scores was explained. Discussion: Patients with RA in mainland China experience impaired physical and mental health. Targeted and culturally sensitive interventions should be strengthened to improve the HRQoL of this population. Essentials in improving the HRQoL are enhancing self-efficacy, relieving fatigue, delaying the onset of disabilities, increasing social support, and controlling disease activity.