Abstract Background Systemic sclerosis (SSc) is a rare autoimmune disease characterized by fibrosis of the skin and the involvement of multiple internal organs. Previous studies reported poorer health-related quality of life (HRQoL) in patients with SSc compared with the general population. However, very little is known about how HRQoL in SSc patients compares with that in patients with other systemic autoimmune diseases, such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Sjogren’s syndrome (SjS). Thus, the main aim of this study was to compare HRQoL in SSc patients, patients with other rheumatic diseases, and the general population. Methods In this cross-sectional study, patients from the rheumatology clinics of Seoul National University Hospital with SSc, RA, SLE, and SjS were enrolled via a random sampling technique. HRQoL was captured by the Short Form (36) health survey (SF-36), the Short Form Six-Dimensional health index (SF-6D), and the EuroQol Five-Dimensional descriptive system (EQ-5D). Demographic characteristics and standardized disease activity for each disease were also obtained. Previously reported data from 600 healthy Koreans were used for the healthy controls. An ANCOVA test was used to compare the SF-36, SF-6D, and EQ-5D values between study subjects with adjustments for age, sex, disease duration, comorbidities, and disease activity status. Results One hundred twenty patients were included in each of the SSc, RA, SLE, and SjS cohorts. Patients with rheumatic diseases had significantly lower SF-36, SF-6D, and EQ-5D scores than healthy controls (all P